The present invention relates to xcex1-substituted carboxylic acid derivatives having excellent insulin resistance improving activity, hypoglycemic activity, anti-inflammatory activity, immunoregulatory activity, aldose reductase inhibiting activity, 5-lipoxygenase inhibiting activity, peroxidized lipid production suppressing activity, PPAR activating activity, anti-osteoporosis activity, leukotrienes antagonistic activity, adipose cell formation promoting activity, cancer cell proliferation suppressing activity or calcium antagonistic activity, to their pharmacologically acceptable esters, to their pharmacologically acceptable amides and to their pharmacologically acceptable salts.
Further, the present invention is directed to preventives and/or therapeutic agents for diseases such as diabetes mellitus, hyperlipemia, obesity, glucose tolerance insufficiency, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataract, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease, etc.), cell injury lesion (e.g. cerebral injury induced by stroke, etc.) caused by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, fervescence, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis, etc.), cancer, osteoporosis, cataract, and so on containing said xcex1-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts as an active ingredient.
Furthermore, this invention concerns a pharmaceutical composition (particularly, preventives and/or therapeutic agents for diabetes mellitus or diabetic complications) containing at least one of sulfonylureas, xcex1-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statin type compounds, squalene synthesis inhibitors, fibrate type compounds, LDL disassimilation promoters, angiotensin II antagonists, angiotensin converting enzyme inhibitors, anti-cancer agents, and RXR activators (RXR agonists) together with said xcex1-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts.
Some of the xcex1-substituted carboxylic acid derivatives of the present application are disclosed in (1) JP Unexamined Pub. H8 (1996)-504194 Gazette, (2) JP Unexamined Pub. H10 (1998)-501222 Gazette, (3) JP Unexamined Pub. H10 (1998)-504808 Gazette, (4) JP Unexamined Pub. H10 (1998)-114751 Gazette, (5) WO 98/31359 Gazette. However, the activities of the compounds described in these Gazettes are as therapeutic agents for anti-platelet aggregation, osteoclast mediating bone resorption suppression, osteoporosis and the like, which are different from those of the present invention.
Further, compounds showing an effect in treating diabetes mellitus or hypoglycemic activity are disclosed in (6) WO 97/31907 Gazette. However, the compounds described in said Gazette may have a benzimidazole ring, one of the structural features of the compounds in the present application also have the same group, but on the benzene ring of said benzimidazole ring in said Gazette there is no substituent or, if any substituent is present there, said substituent is only a lower alkyl group. On the other hand, the compounds of the present invention have comparatively bulky substituent(s) on the benzene ring of the benzimidazole ring, so they are different from the compounds of said Gazette.
Moreover, compounds having an effect in treating diabetes mellitus are disclosed in (7) WO 99/29640 Gazette. However, the compounds described in said Gazette may be xcex1-carboxylic acids having a benzimidazole structure similar to the compounds of the present application, but they are different from the compounds of the present application, because in this case the xcex1-substituent is an amino group or a protecting group thereof such as an alkoxycarbonyl group or an alkoxycarbonyl group which is comparatively easily removable. In addition, the compounds described in said Gazette are different from those of the present application in the nature of their fibroblast proliferation factor antagonism effects.
As the result of investigations for a long time on the search of synthesis and pharmacology of a series of said xcex1-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides and their pharmacologically acceptable salts, the present inventors have found the features that said xcex1-substituted carboxylic acid derivatives have excellent insulin resistance improving activity, hypoglycemic activity, anti-inflammatory activity, immunoregulatory activity, aldose reductase inhibiting activity, 5-lipoxygenase inhibiting activity, peroxidized lipid production suppressing activity, PPAR activating activity, anti-osteoporosis activity, leukotrienes antagonistic activity, adipose cell formation promoting activity, cancer cell proliferation suppressing activity or calcium antagonistic activity, with less side effects and high lipophilic solubility. Thus, the present invention has been established.
The other object of the present invention is to provide preventives and/or therapeutic agents against diseases such as diabetes mellitus, hyperlipemia, obesity, glucose tolerance insufficiency, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataract, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease, etc.), cell injury lesion (e.g. cerebral injury induced by stroke, etc.) caused by aterosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, fervescence, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis, etc.), cancer, osteoporosis, cataract, and so on containing said xcex1-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts as an active ingredient. Further, another object of the present invention is to provide a pharmaceutical composition (particularly, preventives and/or therapeutic agents for diabetes mellitus or diabetic complications) containing at least one of sulfonylureas, xcex1-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statins type compounds, squalene synthesis inhibitors, fibrate type compounds, LDL disassimilation promotors, angiotensin II antagonists, angiotensin converting enzyme inhibitors, anti-cancer agents, and RXR activators (RXR agonists) together with said xcex1-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts. The present invention relates to xcex1-substituted carboxylic acid derivatives having the general formula (I): 
[wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex11 hereafter described), (iv) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (v) C1-C6 alkylsulfonyl group, (vi) C1-C6 halogenoalkylsulfonyl group, (vii) C6-C10 arylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described) or (viii) C7-C16 aralkylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof),
A is a nitrogen atom or xe2x95x90CH-group,
B is an oxygen atom or a sulfur atom,
W1 is a C1-C8 alkylene group,
W2 is a single bond or a C1-C8 alkylene group,
X is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C1-C6 halogenoalkyl group, (iv) C1-C6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C3-C10 cycloalkyl group, (x) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xi) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xii) C1-C7 aliphatic acyl group, (xiii) C4-C11 cycloalkylcarbonyl group, (xiv) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xv) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xvii) carbamoyl group, (xviii) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituting moieties xcex2 described hereafter),
Y is an oxygen atom or S(O)p (wherein p is an integer from 0 to 2),
Z1 is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C1-C6 alkoxy group, (iv) C1-C6 alkylthio group, (v) halogen atom, (vi) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex11 hereafter described), (vii) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (viii) C6-C10 aryloxy group (optionally having 1-5 substituting moieties xcex11 hereafter described), (ix) C7-C16 aralkyloxy group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (x) C3-C10 cycloalkyloxy group, (xi) C3-C10 cycloalkylthio group, (xii) saturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xiii) monocyclic type heteroaromatic ring-oxy group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xiv) C6-C10 arylthio group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (xv) C7-C16 aralkylthio group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (xvi) saturated heterocyclic ring-thio group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xvii) monocyclic type heteroaromatic ring-thio group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xviii) amino group (optionally having 1-2 substituting moieties xcex11 hereafter described) or (xix) hydroxy group,
said substituting moiety xcex11 is a (i) C1-C6 alkyl group, (ii) C1-C6 halogenoalkyl group, (iii) C1-C6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C3-C10 cycloalkyl group, (ix) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (x) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xi) C1-C7 aliphatic acyl group, (xii) C4-C11 cycloalkylcarbonyl group, (xiii) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xiv) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xvi) carbamoyl group, (xvii) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituting moieties xcex2 described hereafter) or (xix) carboxyl group,
said substituting moiety xcex2 is a (i) C1-C10 to alkyl group, (ii) halogen atom, (iii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (iv) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), (v) C1-C7 aliphatic acyl group, (vi) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (vii) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), (viii) C4-C11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (x) carbamoyl group or (xi) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), and
said substituting moiety xcex3 is a C1-C6 alkyl group, C1-C6 halogenoalkyl group, halogen atom or hydroxy group],
the general formula (II) 
[wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex11 hereafter described), (iv) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (v) C1-C6 alkylsulfonyl group, (vi) C1-C6 halogenoalkylsulfonyl group, (vii) C6-C10 arylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described) or (viii) C7-C16 aralkylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof),
A is a nitrogen atom or xe2x95x90CH-group,
B is an oxygen atom or a sulfur atom,
W1 is a C1-C8 alkylene group,
W2 is a single bond or a C1-C8 alkylene group,
X is a (i) hydrogen atom, (ii) C1-C6 alkylene group, (iii) C1-C6 halogenoalkyl group, (iv) C1-C6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C3-C10 cycloalkyl group, (x) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xi) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xii) C1-C7 aliphatic acyl group, (xiii) C4-C11 cycloalkylcarbonyl group, (xiv) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xv) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 described hereafter), (xvii) carbamoyl group, (xviii) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituting moieties xcex2 described hereafter),
Y is an oxygen atom or S(O)p group (wherein p is an integer from 0 to 2)
Z2 is a saturated heterocyclic ring (optionally having 1-5 substituting moieties xcex11 hereafter described), or C6-C10 aryl group (optionally having 1-5 substituting moieties xcex12 hereafter described),
said substituting moiety xcex11 is a (i) C1-C6 alkyl group, (ii) C1-C6 halogenoalkyl group, (iii) C1-C6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C3-C10 cycloalkyl group, (ix) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (x) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xi) C1-C7 aliphatic-acyl group, (xii) C4-C11 cycloalkylcarbonyl group, (xiii) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xiv) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xvi) carbamoyl group, (xvii) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituting moieties xcex2 described hereafter) or (xix) carboxyl group,
said substituting moiety xcex12 is a (i) C3-C10 cycloalkyl group, (ii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (iii) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (iv) C1-C7 aliphatic acyl group, (v) C4-C11 cycloalkylcarbonyl group, (vi) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (vii) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (viii) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), or (ix) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof),
said substituting moiety xcex2 is a (i) C1-C10 alkyl group, (ii) halogen atom, (iii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (iv) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), (v) C1-C7 aliphatic acyl group, (vi) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (vii) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), (viii) C4-C11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (x) carbamoyl group or (xi) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), and
said substituting moiety xcex3 is a C1-C6 alkyl group, C1-C6 halogenoalkyl group, halogen group or hydroxy group],
the general formula (III) 
xe2x80x83[wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex11 hereafter described), (iv) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (v) C1-C6 alkylsulfonyl group, (vi) C1-C6 halogenoalkylsulfonyl group, (vii) C6-C10 arylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described) or (viii) C7-C16 aralkylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof),
A is a nitrogen atom or xe2x95x90CH-group,
B is an oxygen atom or a sulfur atom,
W1 is a C1-C8 alkylene group,
W2 is a single bond or a C1-C8 alkylene group,
X is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C1-C6 halogenoalkyl group, (iv) C1-C6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C3-C10 cycloalkyl group, (x) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xi) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xii) C1-C7 aliphatic acyl group, (xiii) C4-C11 cycloalkylcarbonyl group, (xiv) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xv) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xvii) carbamoyl group, (xviii) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituting moieties xcex2 described hereafter),
Y is an oxygen atom or S(O)p group (wherein p is an integer from 0 to 2),
Z3 is a (i) C1-C6 alkyl group, (ii) C6-C10 aryl group (optionally containing 1-5 substituting moieties xcex11 hereafter described), (iii) C7-C16 aralkyl group (optionally containing 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (iv) C3-C10 cycloalkyl group or (v) saturated heterocyclic ring group (optionally containing 1-5 substituting moieties xcex11 hereafter described),
said substituting moiety xcex11 is a (i) C1-C6 alkyl group, (ii) C1-C6 halogenoalkyl group, (iii) C1-C6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C3-C10 cycloalkyl group, (ix) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (x) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xi) C1-C7 aliphatic acyl group, (xii) C4-C11 cycloalkylcarbonyl group, (xiii) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xiv) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xvi) carbamoyl group, (xvii) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituting moieties xcex2 described hereafter) or (xix) carboxyl group,
said substituting moiety xcex2 is a (i) C1-C10 alkyl group, (ii) halogen atom, (iii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (iv) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), (v) C1-C7 aliphatic acyl group, (vi) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (vii) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), (viii) C4-C11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (x) carbamoyl group or (xi) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), and
said substituting moiety xcex3 is a C1-C6 alkyl group, C1-C6 halogenoalkyl group, halogen atom or hydroxy group], or
the general formula (IV) 
xe2x80x83[wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex11 hereafter described), (iv) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (v) C1-C6 alkylsulfonyl group, (vi) C1-C6 halogenoalkylsulfonyl group, (vii) C6-C10 arylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described) or (viii) C7-C16 aralkylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof),
R4 is a (i) C1-C6 alkyl group, (ii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex11 hereafter described) or (iii) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof),
A is a nitrogen atom or xe2x95x90CH-group,
B is an oxygen atom or a sulfur atom,
W1 is a C1-C8 alkylene group,
W2 is a single bond or a C1-C8 alkylene group,
X is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C1-C6 halogenoalkyl group, (iv) C1-C6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C3-C10 cycloalkyl group, (x) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xi) C7-C16 aralkyl group (optionally having 1-5 substituting moieties, hereafter described on the aryl moiety thereof), (xii) C1-C7 aliphatic acyl group, (xiii) C4-C11 cycloalkylcarbonyl group, (xiv) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xv) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xvii) carbamoyl group, (xviii) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituting moieties xcex2 described hereafter),
Y is an oxygen atom or S(O)p (wherein p is an integer from 0 to 2),
Z4 is a (i) C1-C6 alkoxy group, (ii) C1-C6 alkylthio group, (iii) halogen atom, (iv) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex11 hereafter described), (v) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (vi) C6-C10 aryloxy group (optionally having 1-5 substituting moieties xcex11 hereafter described), (vii) C7-C16 aralkyloxy group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (viii) C3-C10 cycloalkyloxy group, (ix) C3-C10 cycloalkylthio group, (x) saturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xi) monocyclic type heteroaromatic ring-oxy group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xii) C6-C10 arylthio group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xiii) C7-C16 aralkylthio group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof), (xiv) saturated heterocyclic ring-thio group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xv) monocyclic type heteroaromatic ring-thio group (optionally having 1-5 substituting moieties xcex11 hereafter described), (xvi) amino group (optionally having 1 to 2 substituting moieties xcex11 hereafter described) or (xvii) hydroxy group,
said substituting moiety xcex11 is a (i) C1-C6 alkyl group, (ii) C1-C6 halogenoalkyl group, (iii) C1-C6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C3-C10 cycloalkyl group, (ix) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (x) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xi) C1-C7 aliphatic acyl group, (xii) C4-C11 cycloalkylcarbonyl group, (xiii) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xiv) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described), (xvi) carbamoyl group, (xvii) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituting moieties xcex2 described hereafter) or (xix) carboxyl group,
said substituting moiety xcex2 is a (i) C1-C10 alkyl group, (ii) halogen atom, (iii) C6-C10 aryl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (iv) C7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), (v) C1-C7 aliphatic acyl group, (vi) C7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (vii) C8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), (viii) C4-C11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described), (x) carbamoyl group or (xi) C7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof), and
said substituting moiety xcex3 is a C1-C6 alkyl group, C1-C6 halogenoalkyl group, halogen atom or hydroxy group], their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts. Further, Z2O-group in the general formula (II), Z3S-group in the general formula (III) and Z4 in the general formula (IV) is contained in the scope of Z1 in the general formula (I).
When R1, R2, R3, R4, X, Z1, Z3, xcex11 and xcex3 represent a xe2x80x9cC1-C6 alkyl groupxe2x80x9d, said group means a straight or branched alkyl group of 1 to 6 carbon atoms. Examples of said group are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group. C1-C4 alkyl groups are preferable, and C1-C2 alkyl groups are more preferable.
When R1, R2, R3, R4, Z1, Z3 and Z4 represent a xe2x80x9cC6-C10 aryl group (optionally having 1-5 substituting moieties xcex11 described hereafter)xe2x80x9d, when X, xcex11 and xcex12 represent a xe2x80x9cC6-C10 aryl group (optionally having 1-5 substituting moieties xcex2 hereafter described)xe2x80x9d, when xcex2 is a xe2x80x9cC6-C10 aryl group (optionally having 1-5 substituting moieties xcex3 hereafter described)xe2x80x9d, and when Z2 is a xe2x80x9cC6-C10 aryl group (optionally having 1-5 substituting moieties xcex12 described hereafter)xe2x80x9d, said C6-C10 aryl group illustratively includes phenyl, indenyl and naphthyl.
When R1, R2, R3, R4, Z1 and Z3 represent a xe2x80x9cC7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof)xe2x80x9d, when X, xcex11 and xcex12 represent a xe2x80x9cC7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof)xe2x80x9d and when xcex2 is a xe2x80x9cC7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof)xe2x80x9d, said C7-C16 aralkyl group means a C1-C6 alkyl group which is substituted by said C6-C10 aryl group. Examples of said aralkyl moiety are benzyl, naphthylmethyl, indenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl and 6-naphthylhexyl.
When R1, R2 and R3 represent a xe2x80x9cC1-C6 alkylsulfonyl groupxe2x80x9d, said group means a group in which said C1-C6 alkyl group is bonded to the sulfonyl moiety. Examples of said group are methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, isobutanesulfonyl, s-butanesulfonyl, t-butanesulfonyl, pentanesulfonyl, isopentanesulfonyl, 2-methylbutanesulfonyl, neopentanesulfonyl, 1-ethylpropanesulfonyl, hexanesulfonyl, 4-methylpentanesulfonyl, 3-methylpentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylpentanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethylbutanesulfonyl, 2,3-dimethylbutanesulfonyl and 2-ethylbutanesulfonyl. C1-C4 alkylsulfonyl groups are preferable, C1-C2 alkylsulfonyl groups are more preferable, and methanesulfonyl is the most preferable.
When R1, R2 and R3 represent a xe2x80x9cC1-C6 halogenoalkylsulfonyl groupxe2x80x9d, said group means a group in which the alkyl moiety of said C1-C6 alkylsulfonyl group is substituted by one or more halogen atoms. Examples of said group are trifluoromethanesulfonyl, trichloromethanesulfonyl, difluoromethanesulfonyl, dichloro-methanesulfonyl, dibromomethanesulfonyl, fluoromethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, 2,2,2-trichloroethanesulfonyl, 2-bromoethanesulfonyl, 2-chloroethanesulfonyl, 2-fluoroethanesulfonyl, 2-iodoethanesulfonyl, 3-chloropropanesulfonyl, 4-fluorobutanesulfonyl, 6-iodohexanesulfonyl and 2,2-dibromethanesulfonyl.
C1-C4 halogenoalkylsulfonyl groups are preferable, C1-C2 halogenoalkylsulfonyl groups are more preferable, and trifluoromethanesulfonyl is the most preferable.
When R1, R2 and R3 represent a xe2x80x9cC6-C10 arylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described)xe2x80x9d, said C6-C10 arylsulfonyl moiety means a group in which said C6-C10 aryl group is bonded to a sulfonyl moiety. Examples of said C6-C10 arylsulfonyl moiety are phenylsulfonyl, indenylsulfonyl and naphthylsulfonyl.
When R1, R2 and R3 represent a xe2x80x9cC7-C16 aralkylsulfonyl group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof)xe2x80x9d, said C7-C16 aralkylsulfonyl moiety free of the substituting moiety means a group in which said C7-C16 aralkyl is bonded to a sulfonyl moiety. Examples of said C7-C16 aralkylsulfonyl moiety are benzylsulfonyl, naphthylmethylsulfonyl, indenylmethylsulfonyl, 1-phenethylsulfonyl, 2-phenethylsulfonyl, 1-naphthylethylsulfonyl, 2-naphthylethylsulfonyl, 1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl, 1-naphthylpropylsulfonyl, 2-naphthylpropylsulfonyl, 3-naphthylpropylsulfonyl, 1-phenylbutylsulfonyl, 2-phenylbutylsulfonyl, 3-phenylbutylsulfonyl, 4-phenylbutylsulfonyl, 1-naphthylbutylsulfonyl, 2-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl, 4-naphthylbutylsulfonyl, 5-phenylpentylsulfonyl, 5-naphthylpentylsulfonyl, 6-phenylhexylsulfonyl and 6-naphthylhexylsulfonyl.
When W1 and W2 represent a xe2x80x9cC1-C6 alkylene groupxe2x80x9d, said group means a straight or branched chain alkylene group containing 1 to 8 carbon atoms. Examples of said group are methylene, methylmethylene, ethylene, propylene, trimethylene, 1-methylethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, heptamethylene, 1-methylhexamethylene, 2-methylhexamethylene, 5-methylhexamethylene, 3-ethylpentamethylene, octamethylene, 2-methylheptamethylene, 5-methylheptamethylene, 2-ethylhexamethylene, 2-ethyl-3-methylpentamethylene and 3-ethyl-2-methylpentamethylene. The straight chain type C1-C6 alkylene groups are preferable, the straight chain type C1-C4 alkylene groups are more preferable, and the straight chain type C1-C2 alkylene groups are the most preferable.
When X, xcex11 and xcex3 represent a xe2x80x9cC1-C6 halogenoalkyl groupxe2x80x9d, said group means a group in which said C1-C6 alkyl group is substituted by one or more halogen atoms. Examples of said group are trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, and 2,2-dibromethyl. C1-C4 halogenoalkyl groups are preferable, C1-C2 halogenoalkyl groups are more preferable, and trifluoromethyl is the most preferable.
When X, Z1, Z4 and xcex11 represent a xe2x80x9cC1-C6 alkoxy groupxe2x80x9d, said group means a group in which said C1-C6 alkyl group is bonded to oxygen atom. Examples of said group are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, and 2-ethylbutoxy. C1-C4 alkoxy groups are preferable, C1-C2 alkoxy groups are more preferable, and methoxy is the most preferable.
When X, Z1, Z4, xcex11, xcex2 and xcex3 represent a xe2x80x9chalogen atomxe2x80x9d, said group means illustratively a fluorine atom, chlorine atom, bromine atom and iodine atom. Fluorine atom, chlorine atom and bromine atom are preferable, and fluorine atom and chlorine atom are more preferable.
When X, Z3, xcex11 and xcex12 represent a xe2x80x9cC3-C10 cycloalkyl groupxe2x80x9d, said group means a 3 to 10 member saturated cyclic ring type hydrocarbon. Examples of said group are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl. Cyclopropyl, cyclohexyl and adamantyl are preferable, and adamantyl is more preferable.
When X, xcex11, xcex12 and xcex2 represent a xe2x80x9cC1-C7 aliphatic acyl groupxe2x80x9d, said group involves illustratively formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl and crotonoyl. C1-C5 aliphatic acyl groups are preferable, C1-C3 aliphatic acyl groups are more preferable, and acetyl is the most preferable.
When X, xcex11, xcex12 and xcex2 represent a xe2x80x9cC4-C11 cycloalkylcarbonyl groupxe2x80x9d, said group means a group in which said C3-C10 cycloalkyl group is bonded to a carbonyl group. Examples of said group are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, norbornylcarbonyl and adamantylcarbonyl. C4-C7 cycloalkylcarbonyl groups are preferable.
When X, Z2, xcex11 and xcex12 represent a xe2x80x9cC7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described)xe2x80x9d, and when xcex2 represents xe2x80x9cC7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described)xe2x80x9d, said C7-C11 arylcarbonyl moiety means a group in which said C6-C10 aryl group is bonded to a carbonyl group. Examples of said C7-C11 arylcarbonyl moiety are benzoyl, 1-indanecarbonyl, 2-indanecarbonyl and 1- or 2-naphthoyl.
When X, xcex11 and xcex12 represent a xe2x80x9cC8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof)xe2x80x9d and when xcex2 represents xe2x80x9cC8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof)xe2x80x9d, said C8-C17 aralkylcarbonyl moiety means a group in which said C7-C16 aralkyl group is bonded to carbonyl group. Examples of said C8-C17 aralkylcarbonyl moiety are phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, naphthylacetyl, 4-naphthylbutyryl and 6-naphthylhexanoyl.
When X, xcex11 and xcex12 represent a xe2x80x9cmonocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described)xe2x80x9d and when xcex2 represents a xe2x80x9cmonocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described)xe2x80x9d, said monocyclic type heteroaromatic ring-carbonyl moiety means a group in which a 5-7 member heteroaromatic ring containing 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms is bonded to a carbonyl group. Examples of said monocyclic type heteroaromatic ring-carbonyl moiety are 5-member heteroaromatic ring-carbonyl groups such as furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, triazolylcarbonyl and thiadiazolylcarbonyl; 6-member heteroaromatic ring-carbonyl groups such as pyranylcarbonyl, nicotinoyl, isonicotinoyl, pyridazinylcarbonyl, pyrimidinylcarbonyl and pyrazinylcarbonyl; and 7-member heteroaromatic ring-carbonyl groups such as azepinylcarbonyl, etc.
When X, xcex11 and xcex12 represent a xe2x80x9cC7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof)xe2x80x9d and when xcex2 represents a xe2x80x9cC7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex3 hereafter described on the aryl moiety thereof)xe2x80x9d, said C7-C11 arylaminocarbonyl moiety means a group in which the amino group of the aminocarbonyl group is substituted by said C6-C10 aryl group. Examples of said C7-C11 arylaminocarbonyl moiety are phenylaminocarbonyl, indenylaminocarbonyl and naphthylaminocarbonyl.
When Z1 and Z4 represent a xe2x80x9cC1-C6 alkylthio groupxe2x80x9d, it means a group in which said C1-C6 alkyl group is bonded to a sulfur atom. Examples of said group are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio. C1-C4 alkylthio groups are preferable, C1-C2 alkylthio groups are more preferable, and methylthio groups are the most preferable.
When Z1 and Z4 represent a xe2x80x9cC6-C10 aryloxy group (optionally having 1-5 substituting moieties xcex11 hereafter described)xe2x80x9d, said C6-C10 aryloxy moiety means a group in which said C6-C10 aryl group is substituted by an oxygen atom. Examples thereof are phenoxy, indenyloxy and naphthyloxy.
When Z1 and Z4 represent a xe2x80x9cC7-C16 aralkyloxy group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof)xe2x80x9d, said C7-C16 aralkyloxy moiety means a group in which said C7-C16 aralkyloxy is substituted by an oxygen atom. Examples of said C7-C16 aralkyloxy moiety are benzyloxy, naphthylmethloxy, indenylmethyloxy, 1-phenethyloxy, 2-phenethyloxy, 1-naphthylethyloxy, 2-naphthylethyloxy, 1-phenylpropyloxy, 2-phenylpropyloxy, 1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy, 1-naphthylpropyloxy, 2-naphthylpropyloxy, 3-naphthylpropyloxy, 1-phenylbutyloxy, 2-phenylbutyloxy, 3-phenylbutyloxy, 4-phenylbutyloxy, 1-naphthylbutyloxy, 2-naphthylbutyloxy, 3-naphthylbutyloxy, 4-naphthylbutyloxy, 5-phenylpentyloxy, 5-naphthylpentyloxy, 6-phenylhexyloxy and 6-naphthylhexyloxy.
When Z1 and Z4 represent xe2x80x9cC3-C10 cycloalkyloxy groupxe2x80x9d, said group means a group in which said C3-C10 cycloalkyl group is substituted by an oxygen atom. Examples of said group are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, norbornyloxy and adamantyloxy. C3-C6 cycloalkyloxy groups are preferable, and C5-C6 cycloalkyloxy groups are more preferable.
When Z1 and Z4 represent a xe2x80x9cC3-C10 cycloalkylthio groupxe2x80x9d, said group means a group in which said C3-C10 cycloalkyl group is substituted by a sulfur atom. Examples of said group are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, norbornylthio and admantylthio. C3-C6 cycloalkylthio groups are preferable, and C5-C6 cycloalkylthio groups are more preferable.
When Z2 and Z3 represent a xe2x80x9csaturated heterocyclic ring group (optionally having 1-5 substituting moieties xcex11 hereafter described)xe2x80x9d, said saturated heterocyclic ring moiety means a group in which a 4-7 member saturated heterocyclic ring group contains at least one ring atom selected from nitrogen, oxygen and sulfur atoms. Examples of said saturated heterocyclic ring moiety are 4-member saturated heterocyclic rings such as azetidyl, etc.; 5-member saturated heterocyclic rings such as pyrrolidyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidyl, oxazolidyl, isoxazolidyl, thiazolidyl, isothiazolidyl, etc.; 6-member saturated heterocyclic rings such as piperidino, tetrahydropyranyl, tetrahydrothiopyranyl, piperazino, morpholino, thiomorpholino, etc.; and 7-member saturated heterocyclic ring groups such as homopiperazino, etc.
When Z1 and Z4 represent a xe2x80x9csaturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11 hereafter described)xe2x80x9d, said saturated heterocyclic ring-oxy moiety means a group in which said saturated heterocyclic ring is bonded to oxygen atom. Examples of said saturated heterocyclic ring-oxy moiety are 4-member saturated heterocyclic ring-oxy groups such as azetidyloxy, etc.; 5-member saturated heterocyclic ring-oxy groups such as pyrrolidyloxy, tetrahydrofuranyloxy, tetrahydrothiophenyloxy, imidazolidyloxy, oxazolidyloxy, isoxazolidyloxy, thiazolidyloxy, isothiazolidyloxy, etc.; 6-member saturated heterocyclic ring-oxy groups such as piperidinoxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, piperazinoxy, morpholinoxy, thiomorpholinoxy, etc.; and 7-member saturated heterocyclic ring-oxy groups such as homopiperazinoxy, etc.
When Z1 and Z3 represent a xe2x80x9cmonocyclic type heteroaromatic ring-oxy group (optionally having 1-5 substituting moieties xcex11 hereafter described)xe2x80x9d, said monocyclic heteroaromatic ring-oxy moiety means a group in which said 5-7 member heteroaromatic ring containing 1-3 heteroatom(s) selected from the group consisting of oxygen, nitrogen and sulfur atoms is bonded to an oxygen atom. Examples of said saturated heterocyclic ring-oxy moiety are 5-member heteroaromatic ring-oxy groups such as furyloxy, thienyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, 1,2,3-oxadiazolyloxy, triazolyloxy, tetrazolyloxy, thiadiazolyloxy, etc.; 6-member heteroaromatic ring-oxy groups such as pyranyloxy, pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, etc.; and 7-member heterocyclic ring-oxy groups such as azepinyloxy, etc.
When Z1 and Z4 represent a xe2x80x9cC6-C10 arylthio group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof)xe2x80x9d, said C6-C10 arylthio moiety means a group in which said C6-C10 aryl group is substituted by a sulfur atom. Examples of said C6-C10 arylthio moiety are phenylthio, indenylthio and naphthylthio.
When Z1 and Z4 represent a xe2x80x9cC7-C16 aralkylthio group (optionally having 1-5 substituting moieties xcex11 hereafter described)xe2x80x9d, said C7-C16 aralkylthio moiety means a group in which said C7-C16 aralkylthio group is substituted by a sulfur atom. Examples of said C7-C16 aralkylthio moiety are benzylthio, naphthylmethylthio, indenylmethylthio, 1-phenethylthio, 2-phenethylthio, 1 -naphthylethylthio, 2-naphthylethylthio, 1-phenylpropylthio, 2-phenylpropylthio, 3-phenylpropylthio, 1-naphthylpropylthio, 2-naphthylpropylthio, 3-naphthylpropylthio, 1-phenylbutylthio, 2-phenylbutylthio, 3-phenylbutylthio, 4-phenylbutylthio, 1-naphthylbutylthio, 2-naphthylbutylthio, 3-naphthylbutylthio, 4-naphthylbutylthio, 5-phenylpentylthio, 5-naphthylpentylthio, 6-phenylhexylthio and 6-naphthylhexylthio.
When Z1 and Z4 represent a xe2x80x9csaturated heterocyclic ring-thio group (optionally having 1-5 substituting moieties xcex11 hereafter described)xe2x80x9d, said saturated heterocyclic ring-thio moiety means a group in which said saturated heterocyclic ring is bonded to a sulfur atom. Examples of said saturated heterocyclic ring-thio moiety are 4-member saturated heterocyclic ring-oxy groups such as azetidylthio, etc.; 5-member saturated heterocyclic ring-thio groups such as pyrrolidylthio, tetrahydrofuranyl, imidazolidylthio, oxazolidylthio, isoxazolidylthio, thiazolidylthio, isothiazolidylthio, etc.; 6-member saturated heterocyclic ring-thio groups such as piperidinylthio, tetrahydropyranylthio, tetrahydrothiopyranylthio, piperazinylthio, morpholylthio, thiomorpholylthio, etc.; and 7-member saturated heterocyclic ring-thio groups such as homopiperazinothio, etc.
When Z1 and Z4 represent a xe2x80x9cmonocyclic type heteroaromatic ring-thio group (optionally having 1-5 substituting moieties xcex11 hereafter described)xe2x80x9d, said monocyclic heteroaromatic ring-thio moiety means a group in which said 5-7 member heteroaromatic ring containing 1-3 heteroatom(s) selected from the group consisting of oxygen, nitrogen and sulfur atoms is bonded to a sulfur atom. Examples of said saturated heterocyclic ring-thio moiety are 5-member heteroaromatic ring-thio groups such as furylthio, thienylthio, pyrrolylthio, pyrazolylthio, imidazolylthio, oxazolylthio, isoxazolylthio, thiazolylthio, isothiazolyltho, 1,2,3-oxadiazolylthio, triazolylthio, tetrazolylthio, thiadiazolylthio, etc.; 6-member heteroaromatic ring-thio groups such as pyranylthio, pyridylthio, pyridazinylthio, pyrimidinylthio, pyrazinylthio, etc.; and 7-member heterocyclic ring-thio groups such as azepinylthio, etc.
When xcex2 represents a xe2x80x9cC1-C10 alkyl groupxe2x80x9d, said group means a straight chain or branched chain alkyl group of 1-10 carbon atoms. Examples of said group are heptyl, 1-methylhexyl, 2-methylhexyl, nonyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl and 7,7-dimethyloctyl, in addition to those illustrated in the definition of said C1-C6 alkyl group. C1-C6 alkyl groups are preferable, C1-C4 alkyl groups are more preferable, and C1-C2 alkyl groups are the most preferable.
When the substituting moiety xcex2 represents a xe2x80x9cC6-C10 aryl group (optionally having 1-5 substituting moieties xcex3), in view of the definition of said substituting moiety xcex3, examples of said group having the substituting moiety xcex3 are 4-methylphenyl, 4-methylnaphthyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 4-propylphenyl, 4-propylnaphthyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-trifluoromethylnaphthyl, 3,4-ditrifluoromethylphenyl, 2,3,4-tritrifluoromethylphenyl, 4-tetrafluoropropylnaphthyl, 4-fluorophenyl, 4-fluoronaphthyl, 3,4-difluorophenyl, 2,3,4-trifluorophenyl, 4-hydroxyphenyl, 4-hydroxynaphthyl, 3,4-dihydroxyphenyl and 2,3,4-trihydroxyphenyl. As to said group, C6-C10 aryl groups (optionally having 1-3 substituting moieties xcex3) are preferable, phenyl groups (optionally having 1-3 substituting moieties xcex3) are more preferable, and phenyl or 4-trifluoromethylphenyl are the most preferable.
When the substituting moiety xcex2 represents a xe2x80x9cC7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex3 on the aryl moiety thereof)xe2x80x9d, examples of said group having such a substituting moiety are 4-methylbenzyl, 2,3,4-trimethylbenzyl, 4-methylphenethyl, 2,3,4-trimethylphenethyl, 4-(4-methylphenyl)butyl, 2-, 3- or 4-trifluoromethylbenzyl, 3,4-ditrifluoromethylbenzyl, 2,3,4-tritrifluoromethylbenzyl, 4-tetrafluoropropylbenzyl, 4-trifluoromethylphenethyl, 3,4-ditrifluoromethylphenethyl, 2,3,4-tritrifluoromethylphenethyl, 4-tetrafluoropropylphenethyl, 4-(4-trifluoromethylphenyl)butyl, 4-(4-tetrafluoropropyl)butyl, 6-(4-trifluoromethylphenyl)hexyl, 6-(4-tetrafluoropropylphenyl)hexyl, 2-, 3- or 4-trifluoromethylnaphthylmethyl, 4-tetrafluoropropylnaphthylmethyl, 4-(4-trifluoromethylnaphthyl)butyl, 4-(4-tetrafluoropropylnaphthyl)butyl, 4-fluorobenzyl, 2,3,4-trifluorobenzyl, 4-fluorophenethyl, 2,3,4-trifluorophenethyl, 4-(4-fluorophenyl)butyl, 4-hydroxybenzyl, 2,3,4-trihydroxybenzyl, 4-hydroxyphenethyl, 2,3,4-trihydroxyphenethyl and 4-(4-hydroxyphenyl)butyl. As to said group, C7-C16 aralkyl groups (optionally having 1-3 substituting moieties xcex3 on the aryl moiety thereof) are preferable, phenyl-C1-C6 alkyl groups (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety) are more preferable, further phenyl-C1-C6 alkyl groups (optionally having one trifluoromethyl group on the phenyl moiety) are yet more preferable, and phenyl-C1-C2 alkyl groups (optionally having one trifluoromethyl group on the phenyl moiety) are the most preferable.
When the substituting moiety xcex2 represents a xe2x80x9cC7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex3)xe2x80x9d, examples of said group having such a substituting moiety are 4-methylbenzoyl, 1- or 2-(5-methyl)naphthoyl, 4-trifluoromethylbenzoyl, 4-tetrafluoropropylbenzoyl, 1-(5-trifluoromethylindane)-carbonyl, 2-(5-trifluoromethylindane)carbonyl, 2-(6-trifluoromethylindane)carbonyl, 1- or 2-(5-trifluoromethyl)naphthoyl, 4-fluorobenzoyl, 1- or 2-(5-fluoro)naphthoyl, 4-hydroxybenzoyl and 1- or 2-(5-hydroxy)naphthoyl. As said group, C7-C11 arylcarbonyl groups (optionally having 1-3 substituting moieties xcex3) are preferable, benzoyl groups (optionally having 1-3 substituting moieties xcex3) are more preferable, further benzoyl groups (optionally having one substituting moiety xcex3) are yet more preferable, and benzoyl groups (optionally having one substituting moiety, trifluoromethyl) are the most preferable.
When the substituting moiety xcex2 represents a xe2x80x9cC8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties on the aryl moiety thereofxe2x80x9d, examples of said group having such a substituting moiety are 4-methylphenylacetyl, 4-(4-methyl)phenylbutyryl, 6-(methylnaphthyl)hexanoyl, 2-, 3- or 4-trifluoromethylphenylacetyl, 4-tetrafluoropropylphenylacetyl, 4-(4-trifluoromethyl)phenylbutyryl, 6-(4-trifluoromethyl)phenylhexanoyl, 4-trifluoromethylnaphthylacetyl, 6-(trifluoromethylnaphthyl)hexanoyl, 4-fluorophenylacetyl, 4-(4-fluoro)phenylbutyryl, 6-(fluoronaphthyl)hexanoyl, 4-hydroxyphenylacetyl, 4-(4-hydroxy)phenylbutyryl and 6-(hydroxynaphthyl)hexanoyl. As to said group, C8-C17 aralkylcarbonyl groups (optionally having 1-3 substituting moieties xcex3 on the aryl moiety) are preferable, phenyl-C1-C6 alkylcarbonyl groups (optionally having 1-3 substituting moieties xcex3 on the aryl moiety) are more preferable, further phenyl-C1-C6 alkylcarbonyl groups (optionally having one substituting moiety, C1-C6 halogenoalkyl on the aryl moiety) are still more preferable, furthermore phenyl-C1-C6 alkylcarbonyl groups (optionally having one substituting moiety, trifluoromethyl on the aryl moiety) are yet more preferable, and phenylacetyl or 4-trifluoromethylphenylacetyl are the most preferable.
When the substituting moiety xcex2 represents a xe2x80x9cmonocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex3)xe2x80x9d, examples of the group having such a substituting moiety are methylfurylcarbonyl, methylthienylcarbonyl, methylpyrrolylcarbonyl, methylnicotinoyl, trifluoromethylfurylcarbonyl, trifluoromethylthienylcarbonyl, trifluoromethylpyrrolylcarbonyl, trifluoromethyloxazolylcarbonyl, trifluoromethylthiazolylcarbonyl, trifluoromethylnicotinoyl, tetrafluoropropylfurylcarbonyl, tetrafluoropropylthienylcarbonyl, tetrafluoropropylpyrrolylcarbonyl, fluorofurylcarbonyl, fluorothienylcarbonyl, fluoropyrrolylcarbonyl, fluoronicotinoyl, hydroxyfurylcarbonyl, hydroxythienylcarbonyl, hydroxypyrrolylcarbonyl and hydroxynicotinyol. As to said group, monocyclic type heteroaromatic ring-carbonyl groups (optionally having 1-3 substituting moieties xcex3) are preferable, monocyclic type heteroaromatic ring-carbonyl groups (optionally having one substituting moiety xcex3) are more preferable, further monocyclic type heteroaromatic ring-carbonyl groups (optionally having one substituting moiety, trifluoromethyl) are still more preferable, furthermore 5- or 6-member monocyclic type heteroaromatic ring-carbonyl groups (optionally having one substituting moiety, trifluoromethyl) are yet more preferable, and furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or nicotinoyl are the most preferable. When the substituting moiety xcex2 represents a xe2x80x9cC7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex3 on the aryl moiety thereof)xe2x80x9d, examples of said group having such a substituting moiety are 4-methylphenylcarbamoyl, 2,3,4-trimethylphenylcarbamoyl, 1- or 2-(6- or 7-methylnaphthyl)carbamoyl, 2-, 3- or 4-trifluoromethylphenylcarbamoyl, 4-tetrafluoropropylphenylcarbamoyl, 3,4-difluoromethylphenylcarbamoyl, 2,3,4-tritrifluoromethylphenylcarbamoyl, 1- or 2-(6- or 7-trifluoromethylnaphthyl)carbamoyl, 2-(6-tetrafluoropropylnaphthyl)carbamoyl, 4-fluorophenylcarbamoyl, 2,3,4-trifluorophenylcarbamoyl, 1- or 2-(6- or 7-fluoronaphthyl)carbamoyl, 4-hydroxyphenylcarbamoyl, 2,3,4-trihydroxyphenylcarbamoyl and 1- or 2-(6- or 7-hydroxynaphthyl)carbamoyl. As to said group, C7-C11 arylaminocarbonyl groups (optionally having 1-3 substituting moieties xcex3 on the aryl moiety) are preferable, phenylaminocarbonyl groups (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety) are more preferable, further phenylaminocarbonyl groups (optionally having 1-3 C1-C6 halogenoalkyl groups as the substituting moiety xcex3 on the phenyl moiety) are more preferable, and furthermore phenylaminocarbonyl groups (optionally having one trifluoromethyl group as the substituting moiety) are the most preferable.
When X, xcex11 and xcex12 represent a xe2x80x9cC6-C10 aryl group (optionally having 1-5 substituting moieties xcex2) in view of the definition of said xcex2, examples of said group having such a substituting moiety are methylphenyl, acetylphenyl, benzoylphenyl, biphenylyl, methylbiphenylyl, methylnaphthyl, acetylnaphthyl and benzoylnaphthyl. As to said group, C6-C10 aryl groups (optionally having 1-3 substituting moieties xcex2) are preferable, phenyl groups (optionally having 1-3 substituting moieties xcex2) are more preferable, further phenyl groups (optionally having 1 or 2 substituting moieties xcex2) are yet more preferable, and furthermore phenyl groups (optionally having 1 substituting moiety xcex2) are the most preferable.
When X, xcex11 and xcex12 represent a xe2x80x9cC7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex2 on the aryl moiety)xe2x80x9d, examples of said group having such a substituting moiety are methylbenzyl, acetylbenzyl, benzoylbenzyl, biphenylylmethyl, methylbiphenylylmethyl, methylnaphthylmethyl, acetylnaphthylmethyl, benzoylnaphthylmethyl, methylphenethyl, acetylphenethyl, methylnaphthylethyl, acetylnaphthylethyl, methylphenylbutyl, acetylphenylbutyl, methylnaphthylbutyl and acetylnaphthylbutyl. As to said group, C7-C16 aralkyl groups (optionally having 1-3 substituting moieties xcex2 on the aryl moeity) are preferable, phenyl-C1-C6 alkyl groups (optionally having 1-3 substituting moieties xcex2 on the phenyl moiety) are more preferable, further phenyl-C1-C4 alkyl groups (optionally having 1 or 2 substituting moieties xcex2 on the phenyl moiety) are yet more preferable, and furthermore benzyl or phenethyl groups (optionally having one substituting moiety xcex2) are the most preferable.
When X, xcex11 and xcex12 represent a xe2x80x9cC7-C11 arylcarbonyl group (optionally having 1-5 substituting moieties xcex2)xe2x80x9d, examples of said group having such a substituting moiety are methylbenzoyl, biphenylylcarbonyl, acetylbenzoyl, carbamoylbenzoyl, 4-trifluoromethylphenylcarbamoylbenzoyl and trifluoronaphthylcarbonyl. As to said group, C7-C11 arylcarbonyl groups (optionally having 1-3 substituting moieties xcex2) are preferable, benzoyl groups (optionally having 1-3 substituting moieties xcex2) are more preferable, further benzoyl groups (optionally having 1 or 2 substituting moieties xcex2) are yet more preferable, and furthermore benzoyl groups (optionally having one substituting moiety xcex2) are the most preferable.
When X, xcex11 and xcex12 represent a xe2x80x9cC8-C17 aralkylcarbonyl group (optionally having 1-5 substituting moieties xcex2 on the aryl moiety thereof), examples of said group having such a substituting moiety are methylphenylacetyl, acetylphenylacetyl, benzoylphenylacetyl, biphenylylacetyl, carbamoylphenylacetyl, (4-trifluoromethylphenylcarbamoyl)phenylacetyl, 4-(methylphenyl)butyryl, 4-[(4-trifluoromethylphenylcarbamoyl)phenyl]butyryl, methylnaphthylacetyl and carbamoylnaphthylacetyl. As to said group, C8-C17 aralkylcarbonyl groups (optionally having 1-3 substituting moieties xcex2 on the aryl moiety) are preferable, phenyl-C2-C7 alkylcarbonyl groups (optionally having 1-3 substituting moieties xcex2 on the phenyl moiety) are more preferable, further phenyl-C2-C7 alkylcarbonyl groups (optionally having one substituting moiety xcex2 on the phenyl moiety) are yet more preferable, and furthermore phenylacetyl groups (optionally having one substituting moiety xcex2 on the phenyl moiety) are the most preferable.
When X, xcex11 and xcex12 represent a xe2x80x9cmonocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described)xe2x80x9d, examples of said group are methylfurylcarbonyl, methylthienylcarbonyl, methylpyrrolylcarbonyl, methyloxazolylcarbonyl, methylthiazolylcarbonyl, methyltriazolylcarbonyl, methylpyranylcarbonyl, methylnicotinoyl, methylpyridazinylcarbonyl, methylpyrimidinylcarbonyl, acetylfurylcarbonyl, acetylthienylcarbonyl, acetylpyrrolylcarbonyl, acetyloxazolylcarbonyl, acetylthiazolylcarbonyl, acetylnicotinoyl, carbamoylfurylcarbonyl, carbamoylthienylcarbonyl, carbamoylpyrrolylcarbonyl, carbamoyloxazolylcarbonyl, carbamoylthiazolylcarbonyl and carbamoylnicotinoyl. As to said group, monocyclic type heteroaromatic ring-carbonyl groups (optionally having 1-3 substituting moieties xcex2) are preferable, further monocyclic type heteroaromatic ring-carbonyl groups (optionally having 1 or 2 substituting moieties xcex2) are more preferable, furthermore 5- or 6-member monocyclic type heteroaromatic ring-carbonyl groups (optionally having 1 or 2 substituting moieties xcex2) are yet more preferable, and 5- or 6-member monocyclic type heteroaromatic ring-carbonyl groups (optionally having one substituting moiety xcex2) are the most preferable.
When X, xcex11 and xcex12 represent a xe2x80x9cC7-C11 arylaminocarbonyl group (optionally having 1-5 substituting moieties xcex2 hereafter described on the aryl moiety thereof)xe2x80x9d, examples of said group having such a substituting moiety are methylphenylcarbonyl, biphenylylcarbamoyl, acetylphenylcarbamoyl, methylnaphthylcarbamoyl, and acetylnaphthylcarbamoyl. As to said group, C7-C11 arylaminocarbonyl groups (optionally having 1-3 substituting moieties xcex2 on the aryl moiety) are preferable, further phenylaminocarbonyl groups (optionally having 1-3 substituting moieties xcex2 on the phenyl moiety) are more preferable, and phenylaminocarbonyl groups (optionally having one substituting moiety on the phenyl moiety) are the most preferable.
When X and xcex11 represent an xe2x80x9camino group optionally having 1 or 2 substituting moieties xcex2xe2x80x9d, examples of said group are amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, phenylamino, 1- or 2-indenylamino, 1- or 2-naphthylamino, benzylamino, 1- or 2-naphthylmethylamino, 1-indenylmethylamino, 1- or 2-phenethylamino, 1-, 2- or 3-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 5-phenylpentylamino, 6-phenylhexylamino, dibenzylamino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotonoylamino, benzoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino, phenylacetylamino, 3-phenylpropionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino, 6-phenylhexanoylamino, cyclopropionylamino, cyclobutyrylamino, cyclopentanoylamino, cyclohexanoylamino, pyrrolylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino, triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino, isonicotinoylamino, pyrazinylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, N,N-diacetylamino, N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentylamino, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino, N-benzoyl-N-butylamino, N-benzoyl-N-pentylamino, N-benzoyl-N-hexylamino, N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamino, N-hexyl-N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino, N-hexyl-N-phenylacetylamino, N-isobutyl-N-cycloheptanoylamino, N-butyl-N-nicotinoylamino, N-hexyl-N-nicotinoylamino, N-isonicotinoyl-N-hexylamino and 4-trifluoromethylphenylcarbamoylamino. As said group, amino groups optionally having 1 or 2 substituting moieties selected from C1-C10 alkyl, C1-C7 aliphatic acyl and phenylaminocarbonyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety) are preferable, further amino groups optionally having 1 or 2 substituting moieties selected from C1-C6 alkyl, C1-C2 aliphatic acyl and phenylaminocarbonyl group (optionally having one substituting moiety xcex3 on the phenyl moiety) are more preferable, and furthermore amino groups optionally substituted with one phenylaminocarbonyl groups (optionally having one substituting moiety xcex3 on the phenyl moiety) are the most preferable.
When R1, R2, R3, R4, Z1, Z3 and Z4 represent a xe2x80x9cC6-C10 aryl group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, in view of the definition of X, xcex11 and xcex12 described above, examples of said group having such a substituting moiety are methylphenyl, trifluoromethylphenyl, hydroxyphenyl, 4-hydroxy-2,3,5-trimethylphenyl, 3,5-di-t-butyl-4-hydroxyphenyl, adamantylphenyl, 4-amino-3,5-dimethylphenyl, acetylphenyl, methoxyphenyl, benzoylphenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, nitrophenyl, (dimethylamino)phenyl, biphenylyl, methylbiphenylyl, methylnaphthyl, trifluoronaphthyl, hydroxynaphthyl, methoxynaphthyl, fluoronaphthyl and chloronaphthyl. As to said group, C6-C10 aryl groups (optionally having 1-3 substituting moieties xcex11) are preferable, further phenyl groups (optionally having 1-3 substituting moieties xcex11) are more preferable, furthermore phenyl groups (optionally having 1 or 2 substituting moieties xcex11) are yet more preferable, and phenyl groups (optionally having one substituting moiety xcex11) are the most preferable.
When Z2 represents a xe2x80x9cC6-C10 aryl group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, examples of said group are adamantylphenyl, biphenylyl, methylbiphenylyl, benzylphenyl, acetylphenyl, cyclohexylcarbonylphenyl, benzoylphenyl, benzylcarbonylphenyl, pyridinecarbonylphenyl and phenylaminocarbonyl. As to said group, C6-C10 aryl groups (optionally having 1-3 substituting moieties xcex12) are preferable, further phenyl groups (optionally having 1-3 substituting moieties xcex12) are more preferable, furthermore phenyl groups (optionally having 1 or 2 substituting moiety xcex12) are yet more preferable, and phenyl groups (optionally having one substituting moiety xcex12) are the most preferable.
When R1, R2, R3, R4, Z1, Z3 and Z4 represents a xe2x80x9cC7-C16 aralkyl group (optionally having 1-5 substituting moieties xcex11 on the aryl moiety thereof)xe2x80x9d, examples of said group having such a substituting moiety are methylbenzyl, trifluoromethylbenzyl, hydroxybenzyl, 4-hydroxy-2,3,5-trimethylbenzyl, 3,5-di-t-butyl-4-hydroxybenzyl, adamantylbenzyl, 4-amino-3,5-dimethylbenzyl, acetylbenzyl, methoxybenzyl, benzoylbenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, dichlorobenzyl, nitrobenzyl, (dimethylamino)benzyl, biphenylylmethyl, methylbiphenylylmethyl, methylphenethyl, trifluoromethylphenethyl, hydroxyphenethyl, 4-hydroxy-2,3,5-trimethylphenethyl, 3,5-di-t-butyl-4-hydroxyphenethyl, adamantylphenethyl, 4-amino-3,5-dimethylphenethyl, acetylphenethyl, methoxyphenethyl, benzoylphenethyl, fluorophenethyl, difluorophenethyl, chlorophenethyl, nitrophenethyl, (dimethylamino)phenethyl, biphenylylethyl, methylbiphenylyl, methylphenylbutyl, trifluoromethylphenylbutyl, hydroxyphenylbutyl, 4-hydroxy-2,3,5-trimethylphenylbutyl, 3,5-di-t-butyl-4-hydroxyphenylbutyl, adamantylphenylbutyl, 4-amino-3,5-dimethylphenylbutyl, acetylphenylbutyl, methoxyphenylbutyl, fluorophenylbutyl, chlorophenylbutyl, nitrophenylbutyl, (dimethyl)phenylbutyl, biphenylylbutyl, methylnaphthylmethyl, trifluoronaphthylmethyl, hydroxynaphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl and chloropnaphthylmethyl. As to said group, C7-C16 aralkyl groups (optionally having 1-3 substituting moieties xcex11 on the aryl moiety) are preferable, further phenyl-C1-C6 alkyl groups (optionally having 1-3 substituting moieties xcex11 on the phenyl moiety) are more preferable, further phenyl-C1-C6 alkyl groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are yet more preferable, phenyl-C1-C4 alkyl groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are still further preferable, and further phenyl-C1-C2 alkyl groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are the most preferable.
When R1, R2 and R3 represent a xe2x80x9cC6-C10 arylsulfonyl group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, examples of said group having such a substituting moiety are methylphenylsulfonyl, acetylphenylsulfonyl, benzoylphenylsulfonyl, biphenylylsulfonyl, methylbiphenylylsulfonyl, methylnaphthylsulfonyl, acetylnaphthylsulfonyl and benzoylnaphthylsulfonyl. As to said group, C6-C10 arylsulfonyl groups (optionally having 1-3 substituting moieties xcex11) are preferable, further phenylsulfonyl groups (optionally having 1-3 substituting moieties xcex11) are more preferable, and furthermore phenylsulfonyl groups (optionally having one substituting moiety xcex11) are the most preferable.
When R1, R2 and R3 represent a xe2x80x9cC7-C16 aralkylsulfonyl group (optionally having 1-5 substituting moieties xcex11 on the aryl moiety thereof)xe2x80x9d, examples of said group having such a substituting moiety are methylbenzylsulfonyl, acetylbenzylsulfonyl, benzoylbenzylsulfonyl, biphenylylmethylsulfonyl, methylbiphenylylmethylsulfonyl, methylnaphthylmethylsulfonyl, acetylnaphthylmethylsulfonyl, benzoylnaphthylmethylsulfonyl, methylphenethylsulfonyl, acetylphenethylsulfonyl, methylnaphthylethylsulfonyl, acetylnaphthylethylsulfonyl, methylphenylbutylsulfonyl, acetylphenylbutylsulfonyl, methylnaphthylbutylsulfonyl and acetylnaphthylbutylsulfonyl. As to said group, C7-C16 aralkylsulfonyl groups (optionally having 1-3 substituting moieties xcex11 on the aryl moiety) are preferable, further phenyl-C1-C6 alkylsulfonyl groups (optionally having 1-3 substituting moieties xcex11 on the phenyl moiety) are more preferable, furthermore phenyl-C1-C4 alkylsulfonyl groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are yet more preferable, and benzylsulfonyl or phenethylsulfonyl groups (optionally having one substituting moiety xcex1 on the phenyl moiety) are the most preferable.
When Z1 and Z4 represent a xe2x80x9cC6-C10 aryloxy groups (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, examples of said group having such a substituting moiety are methylphenoxy, trifluoromethylphenoxy, hydroxyphenoxy, 4-hydroxy-2,3,5-trimethylphenoxy, 3,5-di-t-butyl-4-hydroxyphenoxy, cyclopropylphenoxy, adamantylphenoxy, cyanophenoxy, nitrophenoxy, 4-amino-3,5-dimethylphenoxy, acetylphenoxy, methoxyphenoxy, benzoylphenoxy, fluorophenoxy, difluorophenoxy, chlorophenoxy, dichlorophenoxy, nitrophenoxy, (dimethylamino)phenoxy, 4-(4-trifluoromethylphenylcarbamoylamino)-3,5-dimethylphenoxy, biphenylyloxy, methylbiphenylyloxy, dimethylaminophenoxy, methylnaphthyloxy, trifluoronaphthyloxy, hydroxynaphthyloxy, methoxynaphthyloxy, fluoronaphthyloxy and chloronaphthyloxy. As to said group, C6-C10 aryloxy groups (optionally having 1-3 substituting moieties xcex11) are preferable, further phenoxy groups (optionally having 1-5 substituting moieties xcex11) are more preferable, furthermore phenoxy groups (optionally having one or two substituting moieties xcex11) are yet more preferable, and phenoxy groups (optionally having one substituting moiety xcex11) are the most preferable.
When Z1 and Z4 represent a xe2x80x9cC7-C16 aralkyloxy group (optionally having 1-5 substituting moieties xcex11 hereafter described on the aryl moiety thereof)xe2x80x9d, examples of said group having such a substituting moiety are methylbenzyloxy, trifluoromethylbenzyloxy, hydroxybenzyloxy, 4-hydroxy-2,3,5-trimethylbenzyloxy, 3,5-di-t-butyl-4-hydroxybenzyloxy, adamantylbenzyloxy, 4-amino-3,5-dimethylbenzyloxy, acetylbenzyloxy, methoxybenzyloxy, benzoylbenzyloxy, fluorobenzyloxy, difluorobenzyloxy, chlorobenzyloxy, dichlorobenzyloxy, nitrobenzyloxy, (dimethylamino)benzyloxy, biphenylylmethoxy, methylbiphenylylmethoxy, methylphenethyloxy, trifluoromethylphenethyloxy, hydroxyphenethyloxy, 4-hydroxy-2,3,5-trimethylphenethyloxy, 3,5-di-t-butyl-4-hydroxyphenethyloxy, adamantylphenethyloxy, 4-amino-3,5-dimethylphenethyloxy, acetylphenethyloxy, methoxyphenethyloxy, benzoylphenethyloxy, fluorophenethyloxy, difluorophenethyloxy, chlorophenethyloxy, nitrophenethyloxy, (dimethylamino)phenethyloxy, biphenylylethyloxy, methylbiphenylylethoxy, methylphenylbutoxy, trifluoromethylphenylbutoxy, hydroxyphenylbutoxy, 4-hydroxy-2,3,5-trimethylphenylbutoxy, 3,5-di-t-butyl-4-hydroxyphenylbutoxy, adamantylphenylbutoxy, 4-amino-3,5-dimethylphenylbutoxy, acetylphenylbutoxy, methoxyphenylbutoxy, fluorophenylbutoxy, chlorophenylbutoxy, nitrophenylbutoxy, (dimethylamino)phenylbutoxy, biphenylbutoxy, methylnaphthylmethoxy, trifluoronaphthylmethoxy, hydroxynaphthylmethoxy, methoxynaphthylmethoxy, fluoronaphthylmethoxy and chloronaphthylmethoxy. As to said group, C7-C16 aralkyloxy groups (optionally having 1-3 substituting moieties xcex11 on the aryl moiety thereof) are preferable, further phenyl-C1-C6 alkyloxy groups (optionally having 1-3 substituting moieties xcex11 on the phenyl moiety) are more preferable, furthermore phenyl-C1-C6 alkyloxy groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are yet more preferable, moreover phenyl-C1-C4 alkyloxy groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are still more preferable, and phenyl-C1-C2 alkyloxy groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are the most preferable.
When Z1 and Z4 represent a xe2x80x9csaturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, said group means a monovalent group mainly derived from a monosaccharide. Said monosaccharides illustratively include pentoses such as arabinose, xylose, ribose, etc., hexoses such as glucose, galactose, mannose, etc., aminosugars such as glucosamine, galactosamine, etc., uronic acids such as glucuronic acid, etc. As to said groups, monovalent groups derived from monosaccharides showing physiological activity in vivo of warm-blooded animals (particularly human beings) are preferable, further monovalent groups derived from an uronic acid are more preferable, and monovalent groups derived from glucuronic acid are particularly preferable.
When Z2 and Z3 represent a xe2x80x9csaturated heterocyclic ring group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, said group means a monovalent group mainly derived by removing the hydroxy group from said monosaccharide. As to said group, monovalent groups derived from monosaccharides showing phyiological activity in vivo of warm-blooded animals (particularly human beings) are preferable, further monovalent groups derived from an uronic acid are more preferable, and monovalent groups derived from glucuronic acid are particularly preferable.
When Z1 and Z4 represent a xe2x80x9cmonocyclic type heteroaromatic ring-oxy group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, examples of said group are fluorofuryloxy, fluorothienyloxy, fluoropyrrolyloxy, fluorooxazolyloxy, fluorothiazolyloxy, fluorotriazolyloxy, fluoropyranyloxy, fluoropyridyloxy, fluoropyridazinyloxy, fluoropyrimidinyloxy, methylfuryloxy, methylthienyloxy, methylpyrrolyloxy, methyloxazolyloxy, methylthiazolyloxy, methylpyridyloxy, methoxyfuryl, methoxythienyl, methoxypyrrolyloxy, methoxyoxazolyloxy, methylthiazolyloxy, methoxypyridyloxy, dimethylaminofuryloxy, dimethylaminoethienyloxy, dimethylaminopyrrolyloxy, dimethylaminooxazolyloxy, dimethylaminothiazolyloxy, and dimethylaminopyridyloxy. As to said group, monocyclic type heteroaromatic ring-oxy groups (optionally having 1-3 substituting moieties xcex11) are preferable, further 5- or 6-member monocyclic type heteroaromatic ring-oxy groups (optionally having one or two substituting moieties xcex11) are more preferable, furthermore 5- or 6-member monocyclic type heteroaromatic ring-oxy groups (optionally having one or two substituting moieties xcex11) are yet more preferable, and 5- or 6-member monocyclic type heteroaromatic ring-oxy groups containing one or more hetero-atom(s) (optionally having one substituting moiety xcex11) are the most preferable.
When Z1 and Z4 represent a xe2x80x9cC6-C10 arylthio group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, examples of said group are methylphenylthio, trifluoromethylphenylthio, hydroxyphenylthio, 4-hydroxy-2,3,5-trimethylphenylthio, 3,5-di-t-butyl-4-hydroxyphenylthio, adamantylphenylthio, 4-amino-3,5-dimethylphenylthio, acetylphenylthio, methoxyphenylthio, benzoylphenylthio, fluorophenylthio, difluorophenylthio, chlorophenylthio, dichlorophenylthio, nitrophenylthio, (dimethylamino)phenylthio, biphenylylthio, methylbiphenylylthio, methylnaphthylthio, trifluoronaphthylthio, hydroxynaphthylthio, methoxynaphthylthio, fluoronaphthylthio, and chloronaphthylthio. As to said group, C6-C10 arylthio groups (optionally having 1-3 substituting moieties xcex11) are preferable, further phenylthio groups (optionally having 1-3 substituting moieties xcex11) are more preferable, furthermore phenylthio groups (optionally having one or two substituting moieties xcex11) are yet more preferable, and phenylthio groups (optionally having one substituting moiety xcex11) are the most preferable.
When Z1 and Z4 represent a xe2x80x9cC7-C16 aralkylthio group (optionally having 1-5 substituting moieties xcex11 on the aryl moiety thereof)xe2x80x9d, examples of said group having such a substituting moiety are methylbenzylthio, trifluoromethylbenzylthio, hydroxybenzylthio, 4-hydroxy-2,3,5-trimethylbenzylthio, 3,5-di-t-butyl-4-hydroxybenzylthio, adamantylbenzylthio, 4-amino-3,5-dimethylbenzylthio, acetylbenzylthio, methoxybenzylthio, benzoylbenzylthio, fluorobenzylthio, difluorobenzylthio, chlorobenzylthio, dichlorobenzylthio, nitrobenzylthio, (dimethylamino)benzylthio, biphenylylmethylthio, methylbiphenylylmethylthio, methylphenethylthio, trifluoromethylphenethylthio, hydroxyphenethylthio, 4-hydroxy-2,3,5-trifluoro-phenethylthio, 3,5-di-t-butyl 4hydroxyphenethylthio, adamantylphenethylthio, 4-amino-3,5-dimethylphenethylthio, acetylphenethylthio, methoxyphenethylthio, benzoylphenethylthio, fluorophenethylthio, difluorophenethylthio, chlorophenethylthio, nitrophenethylthio, (dimethylamino)phenethylthio, biphenylylethylthio, methylbiphenylylethylthio, methylphenylylbutylthio, trifluoromethylphenylbutylthio, hydroxyphenylbutylthio, 4-hydroxy-2,3,5-trimethylphenylbutylthio, 3,5-di-t-butyl-4-hydroxyphenylbutylthio, adamantyl-phenylbutylthio, 4-amino-3,5-dimethylphenylbutylthio, acetylphenylbutylthio, methoxyphenylbutylthio, fluorophenylbutylthio, chlorophenylbutylthio, nitrophenylbutylthio, (dimethylamino)phenylbutylthio, biphenylylbutylthio, methylnaphthylmethylthio, trifluoromethylnaphthylmethylthio, hydroxynaphthylmethylthio, methoxynaphthylmethylthio, fluoronaphthylmethylthio, and chloronaphthylmethylthio. As to said groups, C7-C16 aralkylthio groups (optionally having 1-3 substituting moieties xcex11 on the aryl moiety) are preferable, further phenyl-C1-C6 alkylthio groups (optionally having 1-3 substituting moieties xcex11 on the phenyl moiety) are more preferable, furthermore phenyl-C1-C6 alkylthio groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are yet more preferable, then phenyl-C1-C4 alkylthio groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are still more preferable, and phenyl-C1-C2 alkylthio groups (optionally having one substituting moiety xcex11 on the phenyl moiety) are the most preferable.
When Z1 and Z4 represent a xe2x80x9csaturated heterocyclic ring-thio group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, examples of said group having such a substituting moiety are methylpyrrolidylthio, methoxypyrrolidylthio, methyltetrahydrofuranylthio, methoxytetrahydrofuranylthio, methylpiperidylthio, methoxypiperidylthio, methyltetrahydropyranylthio, methoxytetrahydropyranylthio, methyltetrahydrothiopyranylthio, methoxytetrahydrothiopyranylthio, methylpiperazinylthio, methoxypiperazinylthio, methylmorpholylthio, methoxymorpholylthio, methylthiomorpholylthio and methoxythiomorpholylthio. As to said group, 5- or 6-member saturated heterocyclic ring-thio groups (optionally having 1-5 substituting moieties xcex11) are preferable, further 5- or 6-member saturated heterocyclic ring-thio groups (optionally having 1-3 substituting moieties xcex11) are more preferable, and furthermore 5- or 6-member saturated heterocyclic ring-thio groups (optionally having one substituting moiety xcex11) are the most preferable.
When Z1 and Z4 represent a xe2x80x9cmonocyclic type heteroaromatic ring-thio group (optionally having 1-5 substituting moieties xcex11)xe2x80x9d, examples of said group having the substituting moiety are fluorofurylthio, fluorothienylthio, fluoropyrrolylthio, fluorooxazolylthio, fluorothiazolylthio, fluorotriazolylthio, fluoropyranylthio, fluoropyridylthio, fluoropyridazinylthio, fluoropyrimidinylthio, methylfurylthio, methylthienylthio, methylpyrrolylthio, methyloxazolylthio, methylthiazolylthio, methylpyridylthio, methoxyfurylthio, methoxythienylthio, methoxypyrrolylthio, methoxyoxazolylthio, methoxythiazolylthio, methoxypyridylthio, dimethylaminofurylthio, dimethylaminothienylthio, dimethylaminopyrrolylthio, dimethylaminooxazolylthio, dimethylaminothiazolylthio and dimethylaminopyridylthio. As to said group, 5-7 member monocyclic type heteroaromatic ring-thio groups (optionally having 1-3 subsituting moieties xcex11) are preferable, further 5-6 member monocyclic type heteroaromatic ring-thio groups (optionally having one or two substituting moieties xcex11) are more preferable, furthermore 5 or 6-member monocyclic type heteroaromatic ring-thio groups (optionally having one substituting moiety xcex11) are yet more preferable, and 5- or 6-member monocyclic type heteroaromatic ring-thio groups containing one or two heteroatom(s) (optionally having one substituting moiety xcex11) are the most preferable.
When Z1 and Z4 represent an xe2x80x9camino group (optionally having 1 or 2 substituting moieties xcex11)xe2x80x9d, examples of said group are amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, phenylamino, 1 - or 2-indenylamino, 1- or 2-naphthylamino, diphenylamino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotonoylamino, benzoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino, 2,6-diisopropylbenzoylamino, phenylacetylamino, 3-phenyl-propionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino, 6-phenylhexanoylamino, cyclopropanecarbonylamino, cyclobutanecarbonylamino, cyclopentanecarbonylamino, cyclohexanoylamino, pyrrolylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino, triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino, isonicotinoylamino, pyrazinylcarbonyl-amino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, 4-trifluoromethylphenylcarbamoylamino, N,N-diacetylamino, N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentylamino, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino, N-benzoyl-N-butylamino, N-benzoyl-N-pentylamino, N-benzoyl-N-hexylamino, N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamino, N-hexyl-N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino, N-hexyl-N-phenylacetylamino, N-isobutyl-N-cycloheptanecarbonylamino, N-butyl-N-nictonoylamino, N-hexyl-N-nicotinoylamino, and N-isonicotinoyl-N-hexylamino. As to said group, amino groups (optionally having one or two substituting moieties selected from C1-C6 alkyl, C1-C7 aliphatic acyl, C6-C10 aryl optionally having 1-3 substituting moieties xcex2, C7-C16 aralkyl optionally having 1-3 substituting moieties on the aryl moiety thereof and C7-C11 arylcarbonyl optionally having 1-3 substituting moieties xcex2 on the aryl moiety thereof) are preferable, and further amino groups (optionally having one or two substituting moieties xcex2 selected from C1-C4 alkyl, C1-C2 aliphatic acyl, phenyl optionally having one substituting moiety xcex2, phenyl-C1-C4 alkyl optionally having one substituting moiety xcex2 on the phenyl moiety thereof and benzoyl optionally having one substituting moiety xcex2 on the phenyl moiety thereof) are more preferable.
The xcex1-substituted carboxylic acid derivatives of the compounds (I) to (IV) in the present invention having a carboxyl group can be converted into their salts in a conventional manner. Examples of such salts are alkali metal salts such as the sodium salt, potassium salt or lithium salt; alkaline earth metal salts such as the calcium salt or magnesium salt; metal salts such as the aluminum salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt, etc.; inorganic salts such as the ammonium salt; amine salts like organic salts such as the t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt; N-benzyl-N-phenethylamine salt, piperazine salt or tetramethylammonium salt; and tris(hydroxymethyl)aminomethane salt.
The xcex1-substituted carboxylic acid derivatives of the compounds (I) to (IV) in the present invention can be converted into their salts even in the case of their having any basic moiety such as a pyridyl or quinolyl group and also in the case of having no bases. Examples of such salts are hydrohalogenic acid salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate; lower alkanesulfonic acid salts such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate; arylsulfonic acid salts such as benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as glutamate, aspartate, etc.; organic carboxylic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate; amino acid salts such as ornithine, glutamate, aspartate and the like. Of these, hydrohalogenic acid salts and organic acid salts are preferable. The xcex1-substituted carboxylic acid derivatives of the compounds (I) to (IV) in the present invention can be converted into their pharmacologically acceptable esters in a conventional manner. No special limitation is given to these pharmacologically acceptable esters of the xcex1-substituted carboxylic acid derivatives of the compounds (I) to (IV) as long as they are medically useful and pharmacologically acceptable in the form of the xcex1-substituted carboxylic acid derivatives of the compounds (I) to (IV). The esters of the xcex1-substituted carboxylic acid derivatives of the compounds (I) to (IV) in the present invention illustratively include C1-C6 alkyl substituted by C1-C6 alkyl, C7-C19 aralkyl or C1-C7 aliphatic acyloxy, C1-C6 alkyl substituted by C1-C7 alkyloxycarbonyloxy, C1-C6 alkyl substituted by C5-C7 cycloalkylcarbonyloxy, C1-C6 alkyl substituted by C6-C8 cycloalkyloxycarbonyloxy, C1-C6 alkyl substituted by C7-C11 arylcarbonyloxy, C1-C6 alkyl substituted by C7-C11 aryloxycarbonyloxy and 2-oxo-1,3-dioxolene-4-ylmethyl group having C1-C6 alkyl as a substituent at the 5-position.
Concerning the ester group, C1-C6 alkyl groups include illustratively methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, methylbutyl, dimethylpropyl, ethylpropyl, hexyl, methylpentyl, dimethylbutyl, ethylbutyl, and trimethylpropyl. C1-C4 alkyl groups are preferable, further methyl, ethyl, propyl, isopropyl, butyl or isobutyl are more preferable, and methyl or ethyl are the most preferable.
C7-C19 aralkyl groups includes benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl and benzyl. Benzyl is preferable.
C5-C7 cycloalkyl groups includes cyclopentyl, cyclohexyl and cycloheptyl. Cyclohexyl is preferable.
C6-C10 aryl groups includes phenyl and naphthyl, and phenyl is preferable.
Preferable examples of the ester residue are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetoxymethyl, 1-(acetoxy)ethyl, propionyloxymethyl, 1-propionyloxyethyl, butyryloxymethyl, 1-butyryloxyethyl, 1-isobutyryloxyethyl, valeryloxymethyl, 1-valeryloxyethyl, isovaleryloxymethyl, 1-isovaleryloxyethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl, methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, propoxycarbonyloxymethyl, 1-propoxycarbonyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, butoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl, isobutoxycarbonyloxymethyl, 1-isobutoxycarbonyloxyethyl, t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, cyclopentanecarbonyloxymethyl, 1-cyclopentanecarbonyloxyethyl, cyclopentanecarbonyloxymethyl, 1-cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxymethyl, 1-cyclohexanecarbonyloxyethyl, cyclopentyloxycarbonyloxymethyl, 1-cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, benzoyloxymethyl, 1-benzoyloxyethyl, phenoxycarbonyloxymethyl, 1-phenoxycarbonyloxyethyl and 5-methyl-2-oxo-1,3-dioxolene-4-ylmethyl.
The amides of the xcex1-substituted carboxylic acid derivatives of the compounds (I) to (IV) in the present invention mean the compounds in which the carboxyl group of the xcex1-substituted carboxylic acid derivatives and ammonia are condensed with dehydration. Concretely, they are prepared by converting the carboxyl group into a xe2x80x94CONH2 group.
The compounds of the present invention involve various isomers.
For example, the carbon atom at the 2-position of the xcex1-substituted carboxylic acid derivatives of the compounds (I) to (IV) is asymmetrical, and any asymmetric carbon exists on the substituent. So, optical isomers may exist in the compounds of the invention.
Thus, the xcex1-carbon atom is an asymmetric carbon to which R2, Y and the nitrogen atom are bonded, as a result of which stereoisomers in R conformation and S conformation exist. The present invention involves each isomer or a mixture of isomers in free ratio. Such stereoisomers can be prepared by synthesizing xcex1-substituted carboxylic acid derivatives (I)-(IV) from optically resolved starting compounds or by subjecting once synthesized xcex1-substituted carboxylic acid derivatives (I)-(IV), if desired, to optical resolution by conventional optical resolution methods or separating methods, or by asymmetric synthesis.
Further, when Y represents a sulfoxide group, the sulfur atom becomes an asymmetric center to afford optical isomers. Also in this case, the respective isomers or a mixture in a free ratio are included in the scope of the present invention, and such stereoisomers can be optically resolved by conventional optical resolution methods or separating methods, or they can be also prepared by asymmetric synthesis.
Further, geometric isomers can exist also in the cases of those compounds having any double bond(s).
The present invention includes all these kinds of isomers.
In addition, the compounds (I) to (IV) in the present invention may absorb water, be attached to adsorbed water, be converted into a hydrate or form a solvate by allowing to leave in the atmosphere or by being recrystallized. They are to be included in the present invention.
Furthermore, compounds (I)-(IV) of the present invention may absorb another kind of solvent to give a solvate, which will be included in the present invention. Moreover, compounds which may be converted in vivo by metabolism into the xcex1-substituted carboxylic acid derivatives (I)-(IV) or pharmacologically acceptable salts thereof of the present invention, namely so-called pro-drugs are included also in this invention.
Further, a pharmaceutical composition may be prepared by admixing one of sulfonylureas, xcex1-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statin type compounds, squalene synthesis inhibitors, fibrate type compounds, LDL disassimilation promotors, angiotensin II antagonists, angiotensin converting enzyme inhibitors, anti-cancer agents, and RXR activators together with said xcex1-substituted carboxylic acid derivatives (I)-(IV), their pharmacologically acceptable esters, their pharmacologically acceptable amides and their pharmacologically acceptable salts. The sulfonylureas in the above-described definition mean a drug capable of accelerating insulin excretion and illustratively include tolbutamide, acetohexamide, tolazamide, chlorpropamide, etc.
The xcex1-glucosidase inhibitors above-described mean a drug capable of inhibiting digestive enzymes such as amylase, maltase, xcex1-dextrinase, sucrase, etc. so as to delay the digestion of starch and sucrose, and illustratively include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (international non-proprietary name: voglibose), miglitol, and so on.
The aldose reductase inhibitors in the description above mean a drug capable of inhibiting diabetic complications by inhibiting the rate-determining enzyme at the first step of the polyol route and illustratively includes tolrestat, epalrestat, 2,7-difluoro-spiro (9H-fluoren-9,4xe2x80x2-imidazolindin)-2xe2x80x2,5xe2x80x2-dione (international non-proprietary name: imirestat), 3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolin acetate (international non-proprietary name: zenarestat), 6-fluoro-2,3-dihydro-2xe2x80x2,5xe2x80x2-dioxo-spiro[4H-1-benzopyran4,4xe2x80x2-imidazolidin]-2-carboxamide (SNK-860), zopolrestat, sorbinil, 1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209), and so on.
The biguanides in the description above mean a drug having anaerobic glycolysis promoting activity, peripheral insulin enhancing activity, glucose intestinal absorption suppression activity, hepatic glucose neogenesis suppression activity, aliphatic acid oxidation inhibition activity, and the like, and illustratively include phenformin, metformin, buformin, etc.
The statin type compounds in the description above mean a drug capable of lowering blood cholesterol by inhibiting hydroxymethylglutaryl CoA (HMG-CoA) reductase, and illustratively include pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, celivastatin, fluvastatin, etc.
The squalene synthesis inhibitors in the description above mean a drug capable of lowering blood cholesterol by inhibiting squalene synthesis and illustratively include monopotassium (S)-xcex1-[bis(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl-3-phenoxybenzene-butanesulfonate (BMS-188494), and so on.
The fibrate type compounds in the description above mean a drug capable of lowering blood triglyceride levels by suppressing the synthesis and excretion of triglycerides in the liver and activating lipoprotein lipase, and illustratively include bezafibrate, beclofibrate, binifibrate, cyprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, thefibrate, etc.
The LDL disassimilation promotors in the description above mean a drug capable of lowering blood cholesterol by enhancing LDL (low density lipoprotein) acceptor activity and illustratively include those compounds or salts thereof disclosed in JP Unexamined, Pub. H7 (1995)-316144 Gazette, concretely N-[2-[4-bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl]-7,7-diphenyl-2,4,6-heptatrienoic acid amide, and so on.
The statin type compounds, squalene synthesis inhibitors, fibrate type compounds and LDL disassimilation promotors described above may be replaced by other drugs having blood cholesterol and triglyceride lowering activity. Examples of such drugs are nicotinic acid derivatives such as nicomol, niceritrol, etc.; anti-oxidants such as probucol, etc.; and ion exchange resin derivatives such as cholestylamine resin, etc. The angiotensin II antagonists in the description above mean a drug capable of lowering blood pressure by suppressing strongly hypertension due to angiotensin II.
Examples of such drugs are losartan potassium, candesartan cilexetil, valsartan, termisartan, ormesartan, etc.
The angiotensin converting enzyme inhibitors in the description above mean a drug capable of partially lowering blood sugar in diabetic patients by lowering blood pressure at a time by inhibiting angiotensin-converting enzyme, and illustratively include captopril, enarapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltiprl, perindopril, quinapril, spirapril, temocapril, trandolapril, etc.
Examples of preferable xcex1-substituted carboxylic acid derivatives having the general formula (I) will be shown below.
(1) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C6-C10 aryl group (optionally having 1-3 substituting moieties xcex11), (iv) C7-C16 aralkyl group (optionally having 1-3 substituting moieties xcex11 on the aryl moiety thereof), (v) C1-C4 alkylsulfonyl group or (vi) C1-C6 halogenoalkylsulfonyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(2) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group, (iii) phenyl group (optionally having one substituting moiety xcex11), (iv) phenyl-C1-C2 alkyl group (optionally having 1-3 substituting moieties xcex11 on the phenyl moiety) or (v) C1-C2 alkylsulfonyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(3) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group or (iii) benzyl group (optionally having one substituting moiety xcex11 on the phenyl moiety thereof)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(4) The xcex1-substituted carboxylic acid derivatives (wherein R1 is a C1-C2 alkyl group, R2 is a hydrogen atom, and R3 is a C1-C4 alkyl group or phenyl-C1-C4 alkyl group (optionally having one substituting moiety xcex11 on the phenyl moiety thereof)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(5) The xcex1-substituted carboxylic acid derivatives (wherein R1 is a C1-C2 alkyl group, R2 is a hydrogen atom and R3 is a hydrogen atom), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(6) The xcex1-substituted carboxylic acid derivatives (wherein R1 is a C1-C2 alkyl group, R2 is a hydrogen atom and R3 is a phenyl group (optionally having one substituting moiety xcex11), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(7) The xcex1-substituted carboxylic acid derivatives (wherein R1 is a C1-C2 alkyl group, R2 is a hydrogen atom and R3 is a phenyl group (optionally having one substituting moiety xcex11), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(8) The xcex1-substituted carboxylic acid derivatives (wherein R1 is a C1-C2 alkyl group, R2 is hydrogen atom and R3 is a C1-C2 alkylsulfonyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(9) The xcex1-substituted carboxylic acid derivatives (wherein A is a nitrogen atom), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(10) The xcex1-substituted carboxylic acid derivatives (wherein A is a xe2x95x90CH-group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(11) The xcex1-substituted carboxylic acid derivatives (wherein B is an oxygen atom), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(12) The xcex1-substituted carboxylic acid derivatives (wherein B is a sulfur atom), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(13) The xcex1-substituted carboxylic acid derivatives (wherein W1 is a C1-C6 alkylene group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(14) The xcex1-substituted carboxylic acid derivatives (wherein W1 is a C1-C4 alkylene group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(15) The xcex1-substituted carboxylic acid derivatives (wherein W1 is a C1-C2 alkylene group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(16) The xcex1-substituted carboxylic acid derivatives (wherein W1 is a methylene group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(17) The xcex1-substituted carboxylic acid derivatives (wherein W2 is a single bond or a C1-C6 alkylene group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(18) The xcex1-substituted carboxylic acid derivatives (wherein W2 is a C1-C4 alkylene group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(19) The xcex1-substituted carboxylic acid derivatives (wherein W2 is a C1-C2 alkylene group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(20) The xcex1-substituted carboxylic acid derivatives (wherein W2 is a methylene group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(21) The xcex1-substituted carboxylic acid derivatives (wherein X is a (i) hydrogen atom, (ii) C1-C4 alkyl group, (iii) C1-C2 halogenoalkyl group, (iv) C1-C4 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C1-C5 aliphatic acyl group or (x) amino group (optionally having one substituting moiety xcex2)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(22) The xcex1-substituted carboxylic acid derivatives (wherein X is (i) a hydrogen atom, (ii) C1-C2 alkyl group, (iii) halogen atom, (iv) hydroxy group, (v) C1-C2 aliphatic acyl group or (vi) amino group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(23) The xcex1-substituted carboxylic acid derivatives (wherein X is a hydrogen atom), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(24) The xcex1-substituted carboxylic acid derivatives (wherein Z1 is a (i) C1-C4 alkoxy group, (ii) C1-C4 alkylthio group, (iii) halogen atom, (iv) C6-C10 aryloxy group (optionally having 1-5 substituting moieties xcex11), (v) C7-C16 aralkyloxy group (optionally having 1-3 substituting moieties xcex11 on the aryl moiety), (vi) C6-C10 cycloalkyloxy group, (vii) saturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11), (viii) C6-C10 arylthio group (optionally having 1-3 substituting moieties xcex11), (ix) saturated heterocyclic ring-thio group (optionally having 1-5 substituting moieties xcex11), (x) amino group (optionally having one substituting moiety xcex11) or (xi) hydroxy group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(25) The xcex1-substituted carboxylic acid derivatives (wherein Z1 is a (i) C1-C2 alkoxy group, (ii) C1-C2 alkylthio group, (iii) halogen atom, (iv) phenoxy group (optionally having 1-5 substituting moieties xcex11), (v) saturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11), (vi) phenylthio group (optionally having 1-5 substituting moieties xcex11), (vii) saturated heterocyclic ring-thio group (optionally having 1-5 substituting moieties xcex11), (viii) amino group or (ix) hydroxy group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(26) The xcex1-substituted carboxylic acid derivatives (wherein Z1 is a (i) C1-C2 alkoxy group, (ii) C1-C2 alkylthio group, (iii) phenoxy group (optionally having 1-5 substituting moieties xcex11), (iv) saturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11), (v) phenylthio group (optionally having 1-5 substituting moieties xcex11) or (vi) hydroxy group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(27) The xcex1-substituted carboxylic acid derivatives (wherein Z1 is a (i) C1-C2 alkoxy group, (ii) phenoxy group (optionally having 1-3 substituting moieties xcex11) or (iii) phenylthio group (optionally having 1-3 substituting moieties xcex11), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(28) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a (i) C1-C6 alkyl group, (ii) C1-C2 halogenoalkyl group, (iii) C1-C4 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C6-C10 cycloalkyl group, (ix) C1-C2 aliphatic acyl group, (x) C7-C11 arylcarbonyl group (optionally having 1-3 substituting moieties xcex2), (xi) carbamoyl group, (xii) amino group (optionally having 1 to 2 substituting moieties xcex2) or (xiii) carboxyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(29) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a (i) C1-C4 alkyl group, (ii) C1-C2 halogenoalkyl group, (iii) C1-C2 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) adamantyl group, (ix) benzoyl group (optionally having one substituting moiety xcex2), (x) amino group (optionally having one substituting moiety xcex2) or (xi) carboxyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(30) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a (i) C1-C4 alkyl group, (ii) halogen atom, (iii) hydroxy group, (iv) adamantyl group, (v) benzoyl group, (vi) amino group (optionally having one substituting moiety xcex2) or (vii) carboxyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(31) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a (i) C1-C4 alkyl group, (ii) halogen atom, (iii) hydroxy group or (iv) adamantyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(32) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a C1-C4 alkyl group or a hydroxy group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(33) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a halogen atom or an adamantyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(34) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a hydroxy group or a carboxyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(35) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a C1-C4 alkyl group, benzoyl group or amino group (optionally having one substituting moiety xcex2)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(36) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex11 is a benzoyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(37) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex2 is a (i) C1-C6 alkyl group, (ii) halogen atom, (iii) phenyl group (optionally having 1-3 substituting moieties xcex3), (iv) phenyl-C1-C4 alkyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety), (v) C1-C5 aliphatic acyl group or (vi) phenylaminocarbonyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(38) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex2 is a (i) C1-C4 alkyl group, (ii) halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(39) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex2 is a phenylaminocarbonyl group (optionally having one substituting moiety xcex3 on the phenyl moiety)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(40) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex3 is a (i) C1-C2 alkyl group, (ii) C1-C2 halogenoalkyl group, (iii) halogen atom or (iv) hydroxy group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(41) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex3 is a trifluoromethyl group or a halogen atom), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(42) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex3 is a trifluoromethyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
Further, those compounds in which R1, R2 and R3 are selected from (1)-(8) above, A is selected from (9)-(10) above, B is selected from (11)-(12), W1 is selected from (13)-(16) above, W2 is selected from (17)-(20) above, X is selected from (21)-(23) above, Z1 is selected from (24)-(27) above, xcex11 is selected from (28)-(36) above, xcex2 is selected from (37)-(39) above and xcex3 is selected from (40)-(42) above in the xcex1-substituted carboxylic acid derivatives of the general formula (I) are preferable.
For example, the following compounds are preferable in the xcex1-substituted carboxylic acid derivatives of the general formula (I) above.
(43) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C6 alkyl group, (iii) C6-C10 aryl group (optionally having 1-3 substituting moieties xcex11), (iv) C7-C16 aralkyl group (optionally having 1-3 substituting moieties xcex11 on the aryl moiety thereof), (v) C1-C4 alkylsulfonyl group or (vi) C1-C6 halogenoalkylsulfonyl group,
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a C1-C4 alkylene group,
W2 is a C1-C4 alkylene group,
X is a (i) hydrogen atom, (ii) C1-C4 alkyl group, (iii) C1-C2 halogenoalkyl group, (iv) C1-C4 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C1-C5 aliphatic acyl group or (x) amino group (optionally having one substituting moiety xcex2),
Y is an oxygen atom or S(O)p (wherein p is an integer from 0 to 2),
Z1 is a (i) C1-C4 alkoxy group, (ii) C1-C4 alkylthio group, (iii) halogen atom, (iv) C6-C10 aryloxy group (optionally having 1-5 substituting moieties xcex11), (v) C7-C16 aralkyloxy group (optionally having 1-3 substituting moieties xcex11 on the aryl moiety thereof), (vi) C6-C10 cycloalkyloxy group, (vii) saturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11), (viii) C6-C10 arylthio group (optionally having 1-5 substituting moieties xcex11), (ix) saturated heterocyclic ring-thio group (optionally having 1-5 substituting moieties xcex11), (x) amino group (optionally having one substituting moiety xcex11 hereafter described) or (xi) hydroxy group, said substituting moiety xcex11 is a (i) C1-C6 alkyl group, (ii) C1-C2 halogenoalkyl group, (iii) C1-C4 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C6-C10 cycloalkyl group, (ix) C1-C2 aliphatic acyl group (x) C7-C11 arylcarbonyl group (optionally having 1-3 substituting moieties xcex3), (xi) carbamoyl group, (xii) amino group (optionally having 1 to 2 substituting moieties xcex2) or (xiii) carboxyl group,
said substituting moiety xcex2 is a (i) C1-C6 alkyl group, (ii) halogen atom, (iii) phenyl group (optionally having 1-3 substituting moieties xcex3), (iv) phenyl-C 1-C4 alkyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety thereof), (v) C1-C5 aliphatic acyl group or (vi) phenylaminocarbonyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety thereof), and
said substituting moiety xcex3 is a (i) C1-C2 alkyl group, (ii) C1-C2 halogenoalkyl group, (iii) halogen atom or (iv) hydroxy group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof
(44) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group, (iii) phenyl group (optionally having one substituting moiety xcex11), (iv) phenyl-C1-C2 alkyl group (optionally having 1-3 substituting moieties xcex11 on the phenyl moiety thereof) or (v)
C1-C2 alkylsulfonyl group,
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a C1-C2 alkylene group,
W2 is a C1-C2 alkylene group,
X is a (i) hydrogen atom, (ii) C1-C2 alkyl group, (iii) halogen atom, (iv) hydroxy group, (v) C1-C2 aliphatic acyl group or (vi) amino group,
Y is an oxygen atom or S(O)p group (wherein p is an integer of 0-2),
Z1 is a (i) C1-C2 alkoxy group, (ii) C1-C2 alkylthio group, (iii) halogen atom, (iv) phenoxy group (optionally having 1-5 substituting moieties xcex11), (v) saturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11), (vi) phenylthio group (optionally having 1-5 substituting moieties xcex11), (vii) saturated heterocyclic ring-thio group (optionally having 1-5 substituting moieties xcex11), (viii) amino group or (ix) hydroxy group,
the substituting moiety xcex11 is a (i) C1-C4 alkyl group, (ii) C1-C2 halogenoalkyl group, (iii) C1-C2 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) adamantyl group, (ix) benzoyl group (optionally having one substituting moiety xcex2), (x) amino group (optionally having one substituting moiety xcex2) or (xi) carboxyl group,
the substituting moiety xcex2 is a (i) C1-C4 alkyl group, (ii) halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety), and
the substituting moiety xcex3 is a trifluoromethyl group or a halogen atom), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(45) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group or (iii) benzyl group (optionally having one substituting moiety xcex11 on the phenyl moiety thereof),
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a C1-C2 alkylene group,
W2 is a methylene group,
X is a hydrogen atom,
Y is an oxygen atom or S(O)p group (wherein p is an integer of 0-2),
Z1 is a (i) C1-C2 alkoxy group, (ii) C1-C2 alkylthio group, (iii) phenoxy group (optionally having 1-5 substituting moieties xcex11) (iv) saturated heterocyclic ring-oxy group (optionally having 1-5 substituting moieties xcex11), (v) phenylthio group (optionally having 1-5 substituting moieties xcex11) or (vi) hydroxy group), the substituting moiety xcex11 is a (i) C1-C4 alkyl group, (ii) halogen atom, (iii) hydroxy group, (iv) adamantyl group, (v) benzoyl group, (vi) amino group (optionally having one substituting moiety xcex2) or (vii) carboxyl group,
the substituting moiety xcex2 is a phenylaminocarbonyl group (optionally having one substituting moiety xcex3 on the phenyl moiety thereof), and
the substituting moiety xcex3 is a trifluoromethyl group, pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
Further, preferable embodiments of the xcex1-substituted carboxylic acid derivatives of the general formula (II) above-described will be shown below.
(46) The xcex1-substituted carboxylic acid derivatives (wherein Z2 is a 5- or 6-member saturated heterocyclic ring group (optionally having 1-5 substituting moieties xcex11) or a phenyl group optionally having 1-3 substituting moieties xcex12), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(47) The xcex1-substituted carboxylic acid derivatives (wherein Z2 is a tetrahydropyranyl group (optionally having 1-5 substituting moieties xcex11)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(48) The xcex1-substituted carboxylic acid derivatives (wherein Z2 is a phenyl group (optionally having one substituting moiety xcex12), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(49) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex12 is a (i) C6-C10 cycloalkyl group, (ii) phenyl group (optionally having 1-3 substituting moieties xcex2)), (iii) phenylcarbonyl group (optionally having 1-3 substituting moieties xcex2), or (iv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-3 substituting moieties xcex2)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(50) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex12 is a C6-C10 cycloalkyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(51) The xcex1-substituted carboxylic acid derivatives (wherein the substituting moiety xcex12 is an adamantyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
Further, those compounds in which R1, R2 and R3 are selected from (1)-(8) above, A is selected from (9) or (10) above, B is selected from (11) or (12) above, W1 is selected from (13)-(16) above, W2 is selected from (17)-(20) above, X is selected from (21)-(23) above, Z2 is selected from (46)-(48) above, xcex11 is selected from (28)-(36) above, xcex12 is selected from (49)-(51) above, xcex2 is selected from (37)-(39) above and xcex3 is selected from (40)-(42) above in the xcex1-substituted carboxylic acid derivatives of the general formula (II) are preferable.
For example, the following compounds in the xcex1-substituted carboxylic acid derivatives of the general formula (II) are also preferable.
(52) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group, (iii) phenyl group (optionally having one substituting moiety xcex11), (iv) phenyl-C1-C2 alkyl group (optionally having 1-3 substituting moieties xcex11 on the phenyl moiety thereof) or (v)
C1-C2 alkylsulfonyl group,
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a C1-C4 alkylene group,
W2 is a C1-C4 alkylene group,
X is a (i) hydrogen atom, (ii) C1-C2 alkyl group, (iii) halogen atom, (iv) hydroxy group, (v) C1-C2 aliphatic acyl group or (vi) amino group,
Y is an oxygen atom or S(O)p group (wherein p is an integer of 0-2),
Z2 is a 5- or 6-member saturated heterocyclic ring group (optionally having 1-5 substituting moieties xcex11) or a phenyl group (optionally having 1-3 substituting moieties xcex12),
the substituting moiety xcex11 is a (i) C1-C4 alkyl group, (ii) halogen atom, (iii) hydroxy group, (iv) adamantyl group, (v) benzoyl group, (vi) amino group (optionally having one substituting moiety xcex2) or (vii) carboxyl group,
the substituting moiety xcex12 is a C6-C10 cycloalkyl group,
the substituting moiety xcex2 is a (i) C1-C4 alkyl group, (ii) halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety thereof), and
the substituting moiety xcex3 is a trifluoromethyl group or a halogen atom, pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(53) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group or (iii) benzyl group (optionally having one substituting moiety xcex11 on the phenyl moiety thereof),
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a C1-C2 alkylene group,
W2 is a C1-C2 alkylene group,
X is a hydrogen atom,
Y is an oxygen atom or S(O)p group (wherein p is an integer of 0-2),
Z2 is a tetrahydropyranyl group (optionally having 1-5 substituting moieties xcex11), and the substituting moieties xcex11 is a hydroxy group or a carboxyl group, pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(54) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group or (iii) benzyl group (optionally having one substituting moiety xcex11 on the phenyl moiety thereof),
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a C1-C2 alkylene group,
W2 is a C1-C2 alkylene group,
X is a hydrogen atom,
Y is an oxygen atom or S(O)p group (wherein p is an integer of 0-2),
Z2 is a phenyl group (having one substituting moiety xcex12),
the substituting moiety xcex11 is a halogen atom or an adamantyl group, and the substituting moiety xcex12 is adamantyl, pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
Further, preferable embodiments of the xcex1-substituted carboxylic acid derivatives of the general formula (III) will be shown below.
(55) The xcex1-substituted carboxylic acid derivatives (wherein Z3 is a (i) C1-C4 alkyl group, (ii) C6-C10 aryl group (optionally having 1-3 substituting moieties xcex11) or (iii) C3-C10 cycloalkyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(56) The xcex1-substituted carboxylic acid derivatives (wherein Z3 is a C1-C4 alkyl group, phenyl group (optionally having 1-3 substituting moieties xcex11) or C3-C10 cycloalkyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(57) The xcex1-substituted carboxylic acid derivatives (wherein Z3 is a phenyl group (optionally having 1-3 substituting moieties xcex11)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
Furthermore, those compounds in the xcex1-substituted carboxylic acid derivatives of the general formula (III) in which R1, R2 and R3 are selected from (1)-(8) above, A is selected from (9) or (10) above, B is selected from (11) or (12) above, W1 is selected from (13)-(16) above, W2 is selected from (17)-(20) above, X is selected from (21)-(23) above, Z3 is selected from (55)-(57), xcex11 is selected from (28)-(36) above, xcex2 is selected from (37)-(39) above, and xcex3 is selected from (40)-(42) above are preferable. For examples, the following compounds in the xcex1-substituted carboxylic acid derivatives of the general formula (III) are also preferable.
(58) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group or (iii) benzyl group (optionally having one substituting moiety xcex11 on the phenyl moiety thereof)),
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a C1-C2 alkylene group,
W2 is a C1-C2 alkylene group,
X is a hydrogen atom,
Y is an oxygen atom or S(O)p (wherein p is an integer of 0-2),
Z3 is a (i) C1-C4 alkyl group, (ii) C6-C10 aryl group (optionally having 1-3 substituting moieties xcex11) or (iii) C3-C10 cycloalkyl group, and
the substituting moiety xcex11 is a (i) C1-C4 alkyl group, (ii) halogen atom, (iii) hydroxy group or (iv) adamantyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(59) The xcex1-substituted carboxylic acid derivatives (wherein R1 is a C1-C2 alkyl group, R2 is a hydrogen atom, R3 is a C1-C4 alkyl group or a phenyl-C1-C4 alkyl group (optionally having one substituting moiety xcex11 on the phenyl moiety thereof),
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a methylene group,
W2 is a methylene group,
X is a hydrogen atom,
Y is an oxygen atom or S(O)p (wherein p is an integer of 0-2)
Z3 is a phenyl group (optionally having 1-3 substituting moieties xcex11), and the substituting moiety xcex11 is a C1-C4 alkyl group or a hydroxy group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
Further, preferable embodiments in the xcex1-substituted carboxylic acid derivatives of the general formula (IV) above-described will be shown below.
(60) The xcex1-substituted carboxylic acid derivatives (wherein R4 is a C1-C4 alkyl group or phenyl group (optionally having 1-3 substituting moieties xcex11)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(61) The xcex1-substituted carboxylic acid derivatives (wherein R4 is a phenyl group (optionally having one substituting moiety xcex11)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(62) The xcex1-substituted carboxylic acid derivatives (wherein Z4 is a (i) C1-C4 alkoxy group, (ii) C1-C4 alkylthio group (iii) C6-C10 aryloxy group (optionally having 1-3 substituting moieties xcex11), (iv) benzyloxy group (optionally having 1-3 substituting moieties xcex11 on the phenyl moiety thereof), (v) C6-C10 arylthio group (optionally having 1-3 substituting moieties xcex11) or (vi) benzylthio group (optionally having 1-5 substituting moieties xcex11 on the phenyl moiety thereof)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(63) The xcex1-substituted carboxylic acid derivatives (wherein Z4 is a (i) C1-C4 alkoxy group, (ii) C1-C2 alkylthio group, (iii) phenoxy group (optionally having 1-3 substituting moieties xcex11) (iv) phenylthio group (optionally having 1-3 substituting moieties xcex11)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(64) The xcex1-substituted carboxylic acid derivatives (wherein Z4 is a C1-C2 alkoxy group or a phenoxy group (optionally having 1-3 substituting moieties xcex11)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(65) The xcex1-substituted carboxylic acid derivatives (wherein Z4 is a C1-C2 alkoxy group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(66) The xcex1-substituted carboxylic acid derivatives (wherein Z4 is a phenoxy group (optionally having 1-3 substituting moieties xcex11)), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
Furthermore, those compounds in the xcex1-substituted carboxylic acid derivatives of the general formula (IV) above-described in which R1, R2 and R3 are selected from (1)-(8) above, R4 is selected from (60) or (61) above, A is selected from (9) or (10) above, B is selected from (11) or (12) above, W1 is selected from (13)-(16) above, W2 is selected from (17)-(20) above, X is selected from (21)-(23) above, Z4 is selected from (62)-(66) above, xcex11 is selected from (28)-(36), xcex2 is selected from (37)-(39), and xcex3 is selected from (40)-(42) above are also preferable.
For example, the following compounds in the xcex1-substituted carboxylic acid derivatives of the general formula (IV) above are also preferable.
(67) The xcex1-substituted carboxylic acid derivatives (wherein R1, R2 and R3 are the same or different, and each is a (i) hydrogen atom, (ii) C1-C4 alkyl group or (iii) benzyl group (optionally having one substituting moiety xcex11 on the phenyl moiety thereof)),
R4 is a C1-C4 alkyl group or a phenyl group (optionally having 1-3 substituting moieties xcex11),
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a C1-C2 alkylene group,
W2 is a C1-C2 alkylene group,
X is a (i) hydrogen atom, (ii) C1-C2 alkyl group, (iii) halogen atom, (iv) hydroxy group, (v) C1-C2 aliphatic acyl group or (vi) amino group,
Z4 is a (i) C1-C4 alkoxy group, (ii) C1-C2 alkylthio group, (iii) phenoxy group (optionally having 1-3 substituting moieties xcex11) or (iv) phenylthio group (optionally having 1-3 substituting moieties xcex11), and
the substituting moiety xcex11 is a (i) C1-C4 alkyl group, (ii) halogen atom, (iii) hydroxy group, (iv) adamantyl group, (v) benzoyl group, (vi) amino group (optionally having one substituting moiety xcex2) or (vii) carboxyl group,
the substituting moiety xcex2 is a (i) C1-C4 alkyl group, (ii) halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3 substituting moieties xcex3 on the phenyl moiety thereof), and
the substituting moiety xcex3 is a trifluoromethyl group or a halogen atom), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(68) The xcex1-substituted carboxylic acid derivatives (wherein R1 is a C1-C2 alkyl group,
R2 is a hydrogen atom, R3 is a hydrogen atom,
R4 is a phenyl group (optionally having one substituting moiety xcex11),
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a methylene group,
W2 is methylene group,
X is a hydrogen atom,
Z4 is a C1-C2 alkoxy group, and
the substituting moiety xcex11 is a benzoyl group), pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
(69) The xcex1-substituted carboxylic acid derivatives (wherein R1 is a C1-C2 alkyl group,
R2 is a hydrogen atom, R3 is a hydrogen atom,
R4 is a phenyl group (optionally having one substituting moiety xcex11 ),
A is a xe2x95x90CH-group,
B is an oxygen atom,
W1 is a methylene group,
W2 is a methylene group,
X is a hydrogen atom,
Z4 is a phenoxy group (optionally having 1-3 substituting moieties xcex11), the substituting moiety xcex11 is a C1-C4 alkyl group, a benzoyl group or an amino group (optionally having one substituting moiety xcex2),
the substituting moiety xcex2 is a phenylaminocarbonyl group (optionally having one substituting moiety xcex3 on the phenyl moiety thereof), and
the substituting moiety xcex3 is a trifluoromethyl group),
pharmacologically acceptable esters thereof, pharmacologically acceptable amides thereof or pharmacologically acceptable salts thereof.
Examples of the xcex1-substituted carboxylic acid derivatives of the present invention can be shown in Tables 1-5, but the scope of the invention should not be limited by those compounds. Further, the compounds in Tables 1-5 have each the chemical structure (I-1) to (I-5). The abbreviations in the tables have the following significance.
Ac: acetyl
Ada: adamantyl
Boz: benzoyl
Bu: butyl
iBu: isobutyl,
sBu: s-butyl
tBu: t-butyl,
Bz: benzyl
Byr: butyryl
iByr: isobutyryl
Car: carbamoyl
Et: ethyl
GlcA: xcex2-D-glucopyranuranosyloxy
Hx: hexyl,
iHx: isohexyl
sHx: s-hexyl
cHx: cyclohexyl
Hynyl: hexanoyl
Imid: imidazolyl
Me: methyl
Mor: morpholinyl
Nic: nicotinoyl
iNic: isonicotinoyl
Np: naphthyl
Ph: phenyl
Pip: 1-piperidinyl
Pipra: piperazinyl
Pn: pentyl
cPn: cyclopentyl
cPnc: cyclopentylcarbonyl
Pr: propyl
cPr: cyclopropyl
iPr: isopropyl
Prn: propionyl
Pyr: pyridyl
Pyrd: pyrrolidinyl
TioMor: thiomorpholinylcarbonyl
Tos: p-toluenesulfonyl
Va: valeryl group
E.C.No.: exemplification compound number.
The table above may preferably include the following exemplification compound Nos.:
1-1) 3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid,
1-86) 3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid,
1-87) 4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid,
1-170) 4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid,
1-177) 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid,
1-179) 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionic acid,
3-188) N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,
3-285) 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,
3-299) 4-[6-[4-(4-trifluoromethylphenylureide)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,
5-1) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,
5-4) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,
5-21) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionic acid,
5-22) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionic acid,
5-23) 3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,
5-26) 3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,
5-43) 3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionic acid,
5-45) 3-[4-[6-(xcex2-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-mercaptopropionic acid,
5-48) 3-[4-[6-(xcex2-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylthiopropionic acid,
5-65) 3-[4-[6-(xcex2-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylsulfenylpropionic acid,
5-67) 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,
5-68) 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,
pharmacologically acceptable esters or amides thereof, or pharmacologically acceptable salts thereof.
More preferable are:
1-1) 3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid,
1-86) 3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid,
1-87) 4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid,
1-170) 4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid,
1-177) 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid,
1-179) 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionic acid,
3-188) N-(2-benzoylphenyl)-4(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,
3-285) 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,
3-299) 4-[6-[4-(4trifluoromethylphenylureide)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,
5-1) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,
5-4) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2methylthiopropionic acid,
5-21) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionic acid,
5-22) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionic acid,
5-26) 3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,
5-48) 3-[4-[6-(xcex2-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylthiopropionic acid,
5-67) 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,
5-68) 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,
pharmacologically acceptable esters or amides thereof, or pharmacologically acceptable salts thereof.
Most preferable are:
1-1) 3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid,
1-86) 3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid,
1-179) 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionic acid,
3-188) N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,
3-285) 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,
5-21) 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionic acid,
5-67) 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,
pharmacologically acceptable esters or amides thereof, or pharmacologically acceptable salts thereof.
Compounds having formula (I) of the present invention can be prepared according to the following processes A-S:

wherein
R1, R2, R3, W1, W2, X, Y, A and B independently represent as defined above, Z represents Z1, Z2O-group, Z3S-group or Z4 as described above, Yxe2x80x2 represents Y or Nxe2x80x94R4-group as described above (where R4 represents as defined above), and R represents an ester residue as described above.
In Process A, compound (V) can be allowed to react with water in an inert solvent in the presence of an acid or base to prepare compounds having general formulae (I)-(IV).
Any inert solvent can be used in the reaction above as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; alcohols such as methanol, ethanol or propanol; water; and mixtures thereof. Ethers, alcohols, amides, water and mixtures thereof are preferable, and alcohols and ethers are more preferable. Particularly, toluene and tetrahydrofuran are preferable.
Any acid which can be used as an acid catalyst in conventional reactions may be used in the above-described reaction. Such acids include, but are not limited to, for example: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; Bronsted acids including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; and acidic ion-exchange resins. Inorganic and organic acids (particularly hydrochloric acid, acetic acid or trifluoroacetic acid) are preferable.
Any base which will not have any effect on any other moieties than the target moiety in the compound may be used in the above-described reaction. Such bases include, but are not limited to, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium-t-butoxide; and ammonia such as aqueous ammonia solution or concentrated ammonia-methanol. Alkali metal hydroxides and metal alkoxides (particularly, alkali metal hydroxides and metal alkoxides) are preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to 150xc2x0 C., and preferably at from 0xc2x0 C. to 60xc2x0 C. though the temperature may depend on the starting material compounds, solvents and/or other conditions to be used.
The reaction may typically be carried out for from 30 minutes to 5 days, and preferably from 5 to 72 hours though the reaction time may depend on the starting material compounds, solvents, reaction temperature and/or other conditions to be used.
In this process, when R represents a benzyl group which may be substituted, then compound (V) can be subjected to a catalytic reduction process in inert solvent under atmospheric or higher pressure (preferably under pressure higher than atmospheric) to produce target compounds (I)-(IV).
Any catalyst which can be used in conventional catalytic reduction processes may be used in the above-described catalytic reduction process. Such catalysts include, but are not limited to, for example, palladium-carbon, Raney Nickel, rhodium-aluminum oxide, triphenylphosphine-rhodium oxide, palladium-barium sulfate, palladium black, platinum oxide and platinum black. Palladium-carbon is preferable.
Any inert solvent can be used in the catalytic reduction process above as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol), glycerin, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; organic acids such as acetic acid or trifluoroacetic acid; and mixtures thereof. Ethers, alcohols and organic acids are preferable, and alcohols are more preferable.
The reaction may typically be performed at from 0xc2x0 C. to 100xc2x0 C., and preferably at from 10xc2x0 C. to 50xc2x0 C. though the temperature may depend on the starting material compounds, catalysts, solvents and/or other conditions to be used.
The reaction may typically be carried out for from 30 minutes to 48 hours though the reaction time may depend on the starting material compounds, catalysts, solvents, reaction temperature and/or other conditions to be used.

wherein
R1, R2, R3, W1, W2, X, Yxe2x80x2, Z, A, B and R independently represent as defined above, and Boc group represents t-butoxycarbonyl group.
Process B, which is a process for preparing compounds of general formula (V), can be carried out by allowing compound (VI) to react with compound (VII) and then treating the reaction product with an acid. In other words, in this process, the t-butoxycarbonyl group (the amino protecting group) may be removed by treatment with an acid as in the above-described reaction without purifying the amide compound (the intermediate product), and a ring is then formed.
Alternatively, the present process can also be performed by purifying the intermediate product (VIII) obtained by reaction of compound (VI) with compound (VII) (step B1), and then allowing the intermediate product (VIII) to be contacted with an acid (step B2).
Step B1 can be performed according to any of the following processes (a)-(c).
(a) Acid Halide Process
An acid halide process may be performed by allowing compound (VII) to react with a halogenation agent (e.g., thionyl chloride, thionyl bromide, oxalic chloride, oxalic dichloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride) in an inert solvent to obtain an acid halide, and allowing the acid halide to react with compound (VI) or an acidified salt thereof in an inert solvent in the presence or absence (preferably in the presence) of a base(s).
Bases which may be used in the above-described reaction include, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Organic amines (particularly, triethylamine) are preferable.
Any inert solvent can be used in the above-described reaction as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane. Halogenated hydrocarbons, ethers and amides particularly dichloromethane, chloroform, tetrahydrofuran and dimethylformamide) are preferable.
The reaction temperature may depend on the starting material compounds, agents and/or other conditions to be used though the reaction of the halogenation agent with compound (VII) as well as the reaction of the acid halide with compound (VI) or acidified salt thereof may typically be performed at from xe2x88x9220xc2x0 C. to 150xc2x0 C. Preferably, the reaction of the halogenation agent with compound (VII) may be performed at from xe2x88x9210xc2x0 C. to 100xc2x0 C. while the reaction of the acid halide with compound (VI) or an acidified salt thereof may be performed at from xe2x88x9220xc2x0 C. to 100xc2x0 C.
The reaction time may depend on the starting material compounds, agents, reaction temperature and/or other conditions to be used though the reaction of halogenation agent with compound (VII) as well as the reaction of the acid halide with compound (VI) or an acidified salt thereof may typically be performed for from 30 minutes to 80 hours, and preferably from 1 to 48 hours.
(b) Active Ester Process
An active ester process may be performed by allowing compound (VII) to react with an active esterification agent to prepare an active ester which is then allowed to react with compound (VI) or an acidified salt thereof in an inert solvent in the presence or absence (preferably in the presence) of a base.
The active ester process can be preferably performed in the presence of a condensation agent including, for example: N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxyimide; disulfide compounds such as dipyridyldisulfide; carbodiimide compounds such as dicyclohexylcarbodiimide; carbonyldiimidazole; and triphenylphosphine.
Any inert solvent can be used in the above-described reaction as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane. Ethers and amides (particularly dioxane, tetrahydrofuran and dimethylformamide) are preferable.
Bases which can be used in the above-described reaction include, for example, those which can be used for the acid halide process described above.
The reaction temperature may depend on the starting material compounds, agents and/or other conditions to be used though the active esterification process may be performed at from xe2x88x9270xc2x0 C. to 150xc2x0 C., and preferably at from xe2x88x9210xc2x0 C. to 100xc2x0 C. while the reaction of the active ester with compound (VI) or an acidified salt thereof may be performed at from xe2x88x9220xc2x0 C. to 100xc2x0 C., and preferably at from 0xc2x0 C. to 50xc2x0 C.
The reaction time may depend on the starting material compounds, agents, reaction temperature and/or other conditions to be used though the active esterification reaction as well as the reaction of the active ester with compound (VI) or acidified salt thereof may typically be performed for from 30 minutes to 80 hours, and preferably from 1 to 48 hours.
(c) Mixed Acid Anhydride Process
A mixed acid anhydride process may be performed by allowing compound (VII) to react with a mixed acid anhydration agent in an inert solvent in the presence or absence (preferably in the presence) of a base to prepare a mixed acid anhydride which is then allowed to react with compound (VI) or an acidified salt thereof in an inert solvent.
Bases which may be used in the above-described reaction include, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]-octane (DABCO) or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Organic amines (particularly, triethylamine) are preferable.
Mixed acid anhydration agents which can be used in the above-described reaction include, for example: C1-C4 alkyl halide carbonates such as chloroethyl carbonate or chloroisobutyl carbonate; C1-C5 alkanoyl halides such as pivaloyl chloride; and di-C1-C4 alkyl or di-C6-C14 aryl cyanophosphates such as cyanodiethyl phosphonate or cyanodiphenyl phosphonate. Di-C1-C4 alkyl and di-C6-C14 aryl cyanophosphates (particularly cyanodiethyl phosphonate) are preferable.
Any inert solvent can be used in the above-described reaction for preparing the mixed acid anhydride as long as it will not inhibit the reaction and may dissolve the starting materials to some extent. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane. Ethers and amides (particularly tetrahydrofuran and dimethylformamide) are preferable.
The reaction temperature for preparing mixed acid anhydrides may depend on the starting material compounds, agents and/or other conditions to be used though the reaction may typically be performed at from xe2x88x9250xc2x0 C. to 100xc2x0 C., and preferably from 0xc2x0 C. to 60xc2x0 C.
The reaction time for preparing the mixed acid anhydride may depend on the starting material compounds, agents, reaction temperature and/or other conditions to be used though it may typically be from 30 minutes to 72 hours, and preferably from 1 to 24 hours.
The reaction of the mixed acid anhydride with compound (VI) or an acidified salt thereof may be performed in an inert solvent in the presence or absence (preferably in the presence) of a base. The same bases and inert solvents as those which can be used in the above-described process for preparing the mixed acid anhydride may also be used in this reaction.
The temperature for reaction of the mixed acid anhydride with compound (VI) or acidified salt thereof may depend on the starting material compounds, agents and/or other conditions to be used though it may typically be from xe2x88x9230xc2x0 C. to 100xc2x0 C., and preferably from 0xc2x0 C. to 80xc2x0 C.
The reaction of the mixed acid anhydride with compound (VI) or an acidified salt thereof may typically be performed for from 5 minutes to 24 hours, and preferably from 30 minutes to 16 hours, though the time may depend on the starting material compounds, agents, reaction temperature and/or other conditions to be used.
In this reaction, compound (VI) can be reacted directly with compound (VII) in the presence of a base when a di-C1-C4 alkyl cyanophosphate or a di-C6-C14 aryl cyanophosphate is used.
After reaction is completed, the target compound (VIII) obtained in this step may be isolated from the reaction mixture according to any conventional method. For example, the reaction product may appropriately be neutralized; impurities, if any, may be removed by filtration; then an organic solvent comprising two or more liquids which are not miscible with each other (such as water and ethyl acetate) may be added; the organic phase containing the target compound may be separated, washed with, for example, water, and dried on, for example, magnesium sulfate anhydride, sodium sulfate anhydride, or sodium hydrogen carbonate anhydride; and the solvent may be then removed by distillation.
Step B2 (ring closure using an acid) may be performed by allowing compound (VIII) to react in an inert solvent in the presence of an acid.
Any acid which can be used as an acid catalyst in conventional reactions may be used in this step. Such acids include, but are not limited to, for example: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; Bronsted acids including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; and acidic ion-exchange resins. Inorganic and organic acids (particularly hydrochloric acid, acetic acid and trifluoroacetic acid) are preferable.
Any inert solvent can be used in this step as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol), glycerin, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water; and mixtures thereof. Ethers and amides (particularly dioxane, tetrahydrofuran and dimethylformamide) are preferable.
The reaction temperature may depend on the starting material compounds, acids, solvents and/or other conditions to be used though the reaction may typically be performed at from xe2x88x9220xc2x0 C. to the boiling point, and preferably from 0xc2x0 C. to 100xc2x0 C.
The reaction time may depend on the starting material compounds, acids, solvents, reaction temperature and/or other conditions to be used though the reaction may typically be performed for from 15 minutes to 48 hours, and preferably from 30 minutes to 20 hours.
Step B3 is the substitution of a functional group by xe2x80x94YR3 in compound (VIII). In this step, compound (VIIIxe2x80x3), which corresponds to compound (VIII) where the xe2x80x94YR3 group comprises an alkoxyl, alkylthio or amino group, can be obtained by subjecting compound (VIIIxe2x80x2), which corresponds to compound (VIII) where xe2x80x94YR3 group comprises an xe2x80x94OH group, to any one of the following reactions (i)-(iv): (i) Mitsunobu reaction; (ii) etherification; (iii) alkane (or aryl) sulfonylation followed by thioetherification; or (iv) alkane (or aryl) sulfonylation followed by azido-complexing and then reductive reaction.
In step B3,
(i) Mitsunobu reaction for preparing compound (VIIIxe2x80x2) may be performed in an inert solvent in the presence of a phosphine (preferably tributylphosphine or triphenylphosphine) and an azodicarboxylate compound (preferably diethyl azodicarboxylate or 1,1-dipiperidine azodicarboxylate);
(ii) etherification can be performed in the same manner as in step D1 described below;
(iii) alkane (or aryl) sulfonylation followed by thioetherification can be performed in the same manner as in step F1 described below; and
(iv) alkane (or aryl) sulfonylation followed by azido-complexing and then reductive reaction can be performed in the same manner as in step G1 described below.
Further, the amino compound can be subjected to alkylation using an alkyl halide substantially according to step H1 described later, or to any conventional reductive alkylation using an aldehyde or a ketone, to obtain an alkylamide.

wherein
R2, R3, W1, W2, X, Yxe2x80x2, B and R independently represent as defined above.
In Process C, compound (IX) can be allowed to react in an inert solvent in the presence of an acid to prepare compound (VII).
Any acid which can be used as an acid catalyst in conventional reactions may be used in this process. Such acids include, but are not limited to, for example: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; Bronsted acids including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; and acidic ion-exchange resins. Inorganic and organic acids (particularly hydrochloric acid, acetic acid and trifluoroacetic acid) are preferable.
Any inert solvent can be used in this process as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol), glycerine, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water; and mixtures thereof. Ethers and amides (particularly dioxane, tetrahydrofuran and dimethylformamide) are preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to the boiling point, and preferably from 0xc2x0 C. to 80xc2x0 C. though the reaction temperature may depend on the starting material compounds, acids, solvents and/or other conditions to be used.
The reaction may typically be performed for from 15 minutes to 48 hours, and preferably from 30 minutes to 20 hours though the reaction time may depend on the starting material compounds, acids, solvents, reaction temperature and/or other conditions to be used.

wherein
R2, R3, W1, W2, X, Yxe2x80x2, B and R independently represent as defined above, and Halo group represents any one of the halogen atoms described above.
In Process D, compound (X) can be allowed to react with a halide compound having general formula of R3-Halo in an inert solvent in the presence of a base or silver oxide to prepare compound (IX).
Bases which may be used in this process include, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Alkali metal hydrides (particularly, sodium hydride) are preferable.
Any inert solvent can be used in this process as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and mixtures thereof. Ethers and amides (particularly dioxane, tetrahydrofuran and dimethylformamide) are preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to the boiling point, and preferably from 0xc2x0 C. to 100xc2x0 C. though the reaction temperature may depend on the starting material compounds, acids, solvents and/or other conditions to be used.
The reaction may typically be performed for from 15 minutes to 48 hours, and preferably from 30 minutes to 20 hours though the reaction time may depend on the starting material compounds, bases, solvents, reaction temperature and/or other conditions to be used.

wherein
R2, W1, W2, X, B, R and Halo group independently represent as defined above.
In Process E, compound (XI) can be allowed to react with a halide having general formula (XII) in an inert solvent in the presence of a base or silver oxide to prepare compound (XIII).
Bases which may be used in the above-described reaction include, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alkali metal hydrides and alkali metal carbonates (particularly, sodium hydride, potassium carbonate or cesium carbonate) are preferable.
Any inert solvent can be used in this process as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ketones such as acetone or methyl ethyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and mixtures thereof. Ketones, ethers and amides (particularly, acetone, dioxane, tetrahydrofuran and dimethylformamide) are preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to the boiling point, and preferably from 0xc2x0 C. to 100xc2x0 C. though the reaction temperature may depend on the starting material compounds, acids, solvents and/or other conditions to be used.
The reaction may typically be performed for from 15 minutes to 48 hours, and preferably from 30 minutes to 20 hours though the reaction time may depend on the starting material compounds, acids, solvents, reaction temperature and/or other conditions to be used.

wherein
R2, R3, W1, W2, X, B and R independently represent as defined above.
Process F, which is a process for preparing compound (XIV), can be performed by, in an inert solvent, allowing compound (XII) to react with methanesulfonyl chloride in the presence of a base followed by reaction with a mercaptan having general formula R3SH in the presence of a base.
Bases which may be used in step F1 include, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Organic amines (particularly, triethylamine) are preferable. Bases which can be used in the first step can also be used in the second step of the above-described reaction. Alkali metal hydrides (particularly, sodium hydride) are preferable.
Any inert solvent can be used in the above-described reaction as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and mixtures thereof. Ethers and amides (particularly, dioxane, tetrahydrofuran and dimethylformamide) are preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to the boiling point, and preferably at from 0xc2x0 C. to 100xc2x0 C. though the reaction temperature may depend on the starting material compounds, acids, solvents and/or other conditions to be used.
The reaction may typically be performed for from 15 minutes to 48 hours, and preferably from 30 minutes to 20 hours though the reaction time may depend on the starting material compounds, acids, solvents, reaction temperature and/or other conditions to be used

wherein
R2, R3, W1, W2, X, Y, B and R independently represent as defined above.
In Process G, compound (XIII) can be allowed to react with methanesulfonyl chloride in the presence of a base in an inert solvent, and then with sodium azide to form azide compound which is then reduced to obtain compound (XV).
The same conditions as those used in step F1 may be used for the reaction with methanesulfonyl chloride and the following reaction with sodium azide as well except that base is not required in the second step. Further, the reductive reaction may be performed according to azide-to-amino conversion (i.e., the above described catalytic reduction and reaction with phosphine).

wherein
R2, R3, R4, W1, W2, X, B and R independently represent as defined above.
In Process I, compound (XV) is subjected to alkylation, aralkylation or arylation of the amino group to prepare compound (XVI).
Step H1 may be performed substantially according to any known synthesis process. For example, alkylation or aralkylation of the amino group may be performed by allowing the amino group to react with an alkyl halide or aralkyl halide, while arylation may be performed by allowing the amino group to react with an aryl halide in the presence of a base.
Bases which can be used in step H1 of Process H include, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropyl ethylamine, N-methyl morpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Alkali metal bicarbonates are preferable.

wherein
R2, R3, R4, W1, W2, X, B and R independently represent as defined above.
Process I, which is a process for preparing compound (XVI), can be performed by subjecting compound (XVII) to alkylation, aralkylation or arylation of the amino group as in Process H (step I1) and then to the same reaction as step E1 (step I2). This step may be performed after the amino group is protected by any conventional protecting group.

wherein
R2, W2, X, B and R independently represent as defined above.
In Process J, a ketone or aldehyde having general formula (XIX) is converted to a cyanohydrin which is then subjected to hydrolysis or alcoholysis in the presence of acid to obtain compound (XX).
This process may be performed by using zinc iodide as a catalyst in the presence or absence of an inert solvent.
Compound (XVII) may also be prepared by subjecting a ketone or aldehyde of general formula (XIX) to one of the conventional processes for synthesizing amino acids, e.g. Strecker amino acid synthesis in which a ketone or aldehyde is reacted with hydrogen cyanide and ammonia. 

wherein
R1, Z, A and Boc group independently represent as defined above.
Process K, which is a process for preparing compound (VI), can be performed by allowing compound (XXI) to react with a compound having general formula Zxe2x80x94H in an inert solvent in the presence of a base (step K1) and then reducing the reaction product obtained (step K2).
Bases which may be used in step D1 described above can also be used in step K1 as well. Among all, alkali metal hydrides particularly, sodium hydride) are preferable. The same conditions as those for step D1 described above may also be used in step K1.
Step K2, which is a process for the reduction of a nitro group in an aromatic compound, may be performed according to any conventional process such as catalytic reduction, reduction using a combination of a metal and an acid (e.g., zinc-acetic acid, tin-alcohol or tin-hydrochloric acid) or reaction with sodium hydrosulfite.

wherein
R1, A and Boc group independently represent as defined above.
Process L, which is a process for preparing compound (XXI), can be performed by protecting the amino group in compound (XXIII) by using a protecting group therefor, t-butoxycarbonyl group in an inert solvent in the presence or absence of a base (step L1) and then subjecting the protected compound to alkylation, arylation or aralkylation (step L2).
Step L1 is a process for introduction of a protecting group into the amino group (Boc-lation) in which compound (XXIII) is allowed to react with di-t-butyl dicarbonate in an inert solvent in the presence of a base.
Step L2 is alkylation, arylation or aralkylation of the Boc-protected-amino group which can be performed according to any conventionally known process.
Further, when an amino group is present in Z of the above-described compounds (I)-(IV) and intermediate compound (VI), acylation, sulfonylation, or carbamoylation may be obtained by alkylation, arylation or aralkylation of the amino group or by any other conventionally known process.

wherein
R1, R2, W1, W2, X, Z, A, B, R, Boc and Halo groups independently represent as defined above.
Process M is an alternative process for synthesizing compounds (I)-(III) in which xe2x80x94Yxe2x80x94R3 group is a hydroxy group.
In Step M1, compound (XXV) is allowed to form an acetonide between the hydroxy group and carboxyl group in the molecule to prepare compound (XXVI). Step M1 may be performed by allowing compound (XXV) to react with acetone or 2,2-dimethoxypropane in or without (preferably without) inert solvent in the presence of an acid.
Any acid may be used in the above-described reaction, which can be used as an acid catalyst in conventional reactions. Such acids include, but are not limited to, for example: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; Bronsted acids including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; and acidic ion-exchange resins. Inorganic and organic acids (particularly hydrochloric acid, acetic acid and trifluoroacetic acid) are preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to the boiling point, and preferably from 0xc2x0 C. to 80xc2x0 C. though the reaction temperature may depend on the starting material compounds, acids and/or other conditions to be used.
The reaction may typically be performed for from 15 minutes to 48 hours, and preferably from 30 minutes to 20 hours though the reaction time may depend on the starting material compounds, acids, reaction temperature and/or other conditions to be used.
In Step M2, compound (XXVI) may be allowed to react with compound (XII) in an inert solvent in the presence of a base substantially according to Process E to prepare compound (XXVII).
In Step M3, compound (XXVII) may be allowed to react in an inert solvent in the presence of an acid substantially according to Process C to prepare compound (XXVIII).
In Step M4, compound (XXVIII) may be allowed to react with compound (VI) in an inert solvent in the presence of a condensation agent substantially according to Step B1 to prepare compound (XXIX).
In Step M5, compound (XXIX) may be allowed to react with water or an alcohol in an inert solvent (or the inert solvent may be the water or alcohol) in the presence of an acid substantially according to Step B2 to prepare a compound having general formula (XXX) or (XXXI).
Compounds (I)-(IV) in which Y represents S(O)p group where p represents an integer selected from 0-2 may be synthesized according to the following process.

wherein
R1, R3, W1, W2, X, Z, A, B and R independently represent as defined above.
Process N is a process for preparing compounds (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX) and (XL).
In Step N1, compound (VI) is allowed to react with compound (XXI) substantially according to Step B1 described above to obtain compound (XXIII).
In Step N2, compound (XXXIII) is allowed to react substantially according to Step B2 described above to obtain compound (XXXIV).
In Step N3, compound (XXXIV) is allowed to react substantially according to Step A1 described above to obtain compound (XXXV). Step N3 may be performed by allowing compound (XXXIV) to react with water in an inert solvent in the presence of a base.
Any inert solvent can be used in the above-described reaction as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; alcohols such as methanol, ethanol or propanol; water; and mixtures thereof. Ethers, alcohols, amides, water and mixtures thereof are preferable, alcohols and ethers are more preferable, and alcohols and tetrahydrofuran are most preferable.
Any bases which may not affect any other moieties than the target moiety in the compound can be used in the above-described reaction, including, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and ammonia such as aqueous ammonia solution or concentrated ammonia-methanol. Alkali metal hydroxides and metal alkoxides (particularly, alkali metal hydroxides and metal alkoxides) are preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to 150xc2x0 C., and preferably from 0xc2x0 C. to 100xc2x0 C. though the reaction temperature may depend on the starting material compounds, solvents and/or other conditions to be used.
The reaction may typically be performed for from 30 minutes to 5 days, and preferably from 2 to 72 hours though the reaction time may depend on the starting material compounds, solvents, reaction temperature and/or other conditions to be used.
Step N4, where compound (XXXV) is subjected to esterification to prepare compound (XXXVI), is performed substantially according to step B1 described above except for using an alcohol having the general formula ROH instead of compound (IV) and adapting any one of the following processes(a)-(c): (a) acid halide process; (b) active ester process; or (c) mixed acid anhydration process.
Alternatively, Step N4 may also be performed by allowing compound (XXXV) to react with the alcohol of general formula ROH in an inert solvent or in the alcohol in the presence of an acid. Any inert solvent can be used in the above-described reaction as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; alcohols such as methanol, ethanol or propanol; water; and mixtures thereof. Ethers, alcohols, amides and mixtures thereof are preferable, alcohols and ethers are more preferable, and alcohol and tetrahydrofuran are most preferable.
Any acid may be used in the above-described reaction, which can be used as acid catalyst in conventional reactions. Such acids include, but are not limited to, for example: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; Bronsted acids including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; and acidic ion-exchange resins. Inorganic and organic acids (particularly hydrochloric acid, acetic acid or trifluoroacetic acid) are preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to 150xc2x0 C., and preferably from 0xc2x0 C. to 60xc2x0 C. though the reaction temperature may depend on the starting material compounds, solvents and/or other conditions to be used.
The reaction may typically be performed for from 30 minutes to 5 days, and preferably from 5 to 72 hours though the reaction time may depend on the starting material compounds, solvents, reaction temperature and/or other conditions to be used.
In step N5, compound (XXVI) may be allowed to react with a compound having general formula R3-Halo (where R3 is not hydrogen) substantially according to Step D1 described above to obtain compound (XXXVII).
In step N6, compound (XXXVII) may be subjected to ester hydrolysis substantially according to Step A1 described above to obtain compound (XXXVI).
In step N7, compound (XXXVIII) may be allowed to react with ammonia substantially according to Step B1 described above to obtain compound (XXXIX).
In step N8, compound (XXXV) may be allowed to react with ammonia substantially according to Step B1 described above to obtain compound (XL).
In step N9, compound (XL) may be allowed to react with a compound having general formula R3-Halo (where R3 is not hydrogen) substantially according to Step D1 described above to obtain compound (XXXIX).

wherein
R1, R3, W1, W2, X, Z, A, B and R independently represent as defined above.
Process O is a method for preparing compounds (XLI), (XLII), (XLIII), (XLIV), (XLV) and (XLVI) by oxidization of a sulfide.
In Step O1, compound (XXXVII) is allowed to react with a peroxide such as m-chloroperoxybenzoic acid, hydrogen peroxide or t-butylhydroperoxide in an inert solvent in the presence or absence of a base to obtain compounds (XLI) and (XLII). Any inert solvent can be used in the above-described reaction as long as it is inert in the reaction. Such inert solvents include, but are not limited to, for example: aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; alcohols such as methanol, ethanol or propanol; water; and mixtures thereof. Halogenated hydrocarbons, alcohols, amides, and mixtures thereof are preferable, alcohols and halogenated hydrocarbons are more preferable, and alcohols and dichloromethane are most preferable.
Any bases which may not affect any other moieties than the target moiety in the compound can be used in the above-described reaction, including, for example: alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide; and ammonia such as aqueous ammonia solution or concentrated ammonia-methanol. Alkali metal carbonates and alkali metal bicarbonates are preferable, and alkali metal bicarbonates are more preferable.
The reaction may typically be performed at from xe2x88x9220xc2x0 C. to 150xc2x0 C., and preferably from 0xc2x0 C. to 60xc2x0 C. though the reaction temperature may depend on the starting material compounds, solvents and/or other conditions to be used.
The reaction may typically be performed for from 1 minute to 1 day, and preferably from 5 minutes to 2 hours though the reaction time may depend on the starting material compounds, solvents, reaction temperature and/or other conditions to be used.
Step O2, which is a process for preparing compounds (XLIII) and (XLIV), can be performed by allowing compound (XXXVIII) to react with a peroxide such as m-chloroperoxybenzoic acid, hydrogen peroxide or t-butyl hydroperoxide in an inert solvent in the presence or absence of a base substantially according to Step O1 above.
Step O3, which is a process for preparing compounds (XLV) and (XLVI), can be performed by allowing compound (XXXIX) to react with a peroxide such as m-chloroperoxybenzoic acid, hydrogen peroxide or t-butyl hydroperoxide in an inert solvent in the presence or absence of a base substantially according to Step O1 above.

wherein
R1, R3, W1, W2, X, Z, A, B and R independently represent as defined above, Zxe2x80x2 represents a benzyloxy group within the definition of Z, Zxe2x80x3 represents a saturated heterocyclic oxy group (which may have 1-5 substitution moieties xcex11) within the definition of Z where the substitution moiety or moieties xcex11 are protected, and Zxe2x80x2xe2x80x3 represents a saturated heterocyclic oxy group (which may have 1-5 substitution moieties xcex11) within the definition of Z.
Process P is a process for preparing compounds having general formula (I) according to the present invention where Z represents a saturated heterocyclic oxy group (which may have 1-5 substitution moieties xcex11), i.e., compounds (LI), (LII), (LIII), (LIV), (LV) and (LVI).
In Step P1, compound (XXIIxe2x80x2) where Zxe2x80x2 represents a benzyloxy group is allowed to react in an inert solvent substantially according to Step K2 described above to obtain compound (XLVII).
In Step P2, compound (XLVII) is allowed to react with compound (XXXII) in an inert solvent substantially according to Step B1 described above to obtain compound (XLVIII).
In Step P3, compound (XLVIII) is allowed to react in an inert solvent substantially according to Step B2 described above to obtain compound (XLIX).
In Step P4, compound (XLIX) is allowed to react with a compound having a Z group protected by substitution moiety or moieties xcex11 (e.g., methyl 1,2,3,4-tetra-O-acetyl-xcex2-D-glucopyranuronate) in an inert solvent substantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem. Pharm. Bull. 39(8), 2124-2125 (1991) to obtain compound (L).
In Step P5, compound (L) is subjected to hydrolysis in an inert solvent substantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem. Pharm. Bull. 39(8), 2124-2125 (1991) to obtain compound (LI).
In Step P6, compound (L) is subjected to hydrolysis in an inert solvent substantially according to Step A1 described above to obtain compound (LII).
In Step P7, compound (LI) is subjected to hydrolysis in an inert solvent substantially according to Step A1 described above to obtain compound (LII).
In Step P8, compound (LII) is allowed to react with ammonia in an inert solvent substantially according to Step B1 described above to obtain compound (LIII).
In Step P9, compound (LIII) is allowed to react with a compound having general formula R3-Halo (where R3 is not hydrogen) in an inert solvent substantially according to Step D1 described above to obtain compound (LIV).
In Step P10, compound (LII) is subjected to esterification substantially according to Step N4 described above to obtain compound (LV).
In Step P11, compound (LV) is allowed to react with a compound having general formula R3-Halo (where R3 is not hydrogen) in an inert solvent substantially according to Step D1 described above to obtain compound (LVI).

wherein
R1, R3, W1, W2, X, Zxe2x80x2xe2x80x3, A, B and R independently represent as defined above except that R3 is not hydrogen.
In Process Q, sulfide compounds (LVII) and (LVIII) are prepared, and then compounds (LIX), (LX), (LXI), (LXII), (LXIII) and (LXIV) are prepared therefrom as well as from the sulfide compound (LVI) by oxidizing the sulfide compounds (LVI)-(LVIII) in the same manner as described in Process O.
In Step Q1, compound (LVI) is subjected to hydrolysis in an inert solvent substantially according to Step A1 described above to obtain compound (LVII).
In Step Q2, compound (LVII) is allowed to react with ammonia in an inert solvent substantially according to Step B1 described above to obtain compound (LVIII).
Step Q3, which is a process for preparing compounds (LIX) and (LX), can be performed by allowing compound (LVI) to react with a peroxide such as m-chloroperoxybenzoic acid, hydrogen peroxide or t-butyl hydroperoxide in an inert solvent in the presence or absence of a base substantially according to Step O1 above.
Step Q4, which is a process for preparing compounds (LXI) and (LXII), can be performed by allowing compound (LVII) to react with a peroxide such as m-chloroperoxybenzoic acid, hydrogen peroxide or t-butyl hydroperoxide in inert solvent in the presence or absence of a base substantially according to Step O1 above.
Step Q5, which is a process for preparing compounds (LXIII) and (LXIV), can be performed by allowing compound (LVIII) to react with a peroxide such as m-chloroperoxybenzoic acid, hydrogen peroxide or t-butyl hydroperoxide in an inert solvent in the presence or absence of a base substantially according to Step O1 above.
Alternatively, compounds (I)-(IV) according to the present invention where Z represents a saturated heterocyclic oxy group (which may have 1-5 substitution moieties xcex11) can also be synthesized according to the following process.

wherein
R1, R2, R3, W1, W2, X, Yxe2x80x2, Zxe2x80x3, Zxe2x80x2xe2x80x3, A, B and R independently represent as defined above.
Process R is a process for preparing compounds having general formula (I) or (IV) according to the present invention where Z represents a saturated heterocyclic oxy group (which may have 1-5 substitution moieties xcex11) which may be protected, i.e., compounds (LXVII), (LXVIII), (LXIX) or (LXXII).
In Step R1, compound (XLVII) is allowed to react with compound (VII) in an inert solvent substantially according to Step B1 described above to obtain compound (LXV).
In Step R2, compound (LXV) is allowed to react in an inert solvent substantially according to Step B2 described above to obtain compound (LXVI).
In Step R3, compound (LXVI) is allowed to react with a compound having a Z group protected by substitution moiety or moieties xcex11 (e.g., methyl 1,2,3,4-tetra-O-acetyl-xcex2-D-glucopyranuronate) in an inert solvent substantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem. Pharm. Bull. 39 (8), 2124-2125 (1991) to obtain compound (LXVII).
In Step R4, compound (LXVII) is subjected to hydrolysis in an inert solvent substantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem. Pharm. Bull. 39 (8), 2124-2125 (1991) to obtain compound (LXVIII).
In Step R5, compound (LXVIII) is allowed to react with ammonia in an inert solvent substantially according to Step B1 described above to obtain compound (LXIX).
In Step R6, compound (LXVI) is subjected to hydrolysis in an inert solvent substantially according to Step A1 described above to obtain compound (LXX).
In Step R7, compound (LXX) is allowed to react with ammonia in an inert solvent substantially according to Step B1 described above to obtain compound (LXXI).
In Step R8, compound (LXXI) is allowed to react with a compound having a Z group protected by substitution moiety or moieties xcex11 (e.g., methyl 1,2,3,4-tetra-O-acetyl-xcex2-D-glucopyranuronate) in an inert solvent substantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem. Pharm. Bull. 39 (8), 2124-2125 (1991) to obtain compound (LXXII).
In Step R9, compound (LXXII) is subjected to hydrolysis in an inert solvent substantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem. Pharm. Bull. 39 (8), 2124-2125 (1991) to obtain compound (LXIX).
Compounds (I)-(IV) where Z represents a hydroxy group can be synthesized according to the following process.
Process S is a process for preparing compounds (XXXV)-(XL) obtained in Process N and compounds (XXXVI)-(XLVI) obtained in Process O where Z represents a hydroxy group.
Compounds (VI) and (XXVII), which are starting materials in Processes N and O, where Z represents a hydroxy group can be subjected to reactions according to Processes N and O to obtain compounds (XXXV)-(XL) and (XLI)-(XLVI) where Z represents a hydroxy group.
Compound (VI) where Z represents a hydroxy group (i.e., compound (XLVI)) can be prepared according to step P1 described above.
Alternatively, starting material compounds having a substitution moiety or moieties protected may be used instead of those shown in the above-described chemical synthesis pathways and after reactions the protecting group or groups can be removed to obtain the target compounds shown in the pathways.
For example, when substitution moiety xcex3 represents a hydroxy group, compounds which have protected hydroxy group(s) can be subjected to the above-described chemical reactions and then the protecting group(s) can be removed to obtain the target compounds shown in the above-described chemical synthesis pathways.
After completion of the reactions, the target compounds obtained in the respective steps may be collected from the reaction mixtures according to any conventional method. For example, the target compound can be collected by: appropriately neutralizing the reaction products; removing, if any, insoluble materials by filtration; then adding organic solvents which are not miscible with water (e.g. ethyl acetate); separating the organic phase containing the target compound which is then washed with, for example, water, and dried on anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and removing solvent by distillation. The target compounds can be separated and purified by a suitable combination of any conventional methods for separation/purification of organic compounds such as recrystallization and reprecipitation, chromatography using appropriate eluant(s).
Further, the compounds according to the present invention can be obtained according, for example, to the conventional method described below.
Physiologically active compounds (e.g. compounds disclosed in Japanese Patent Application Laid-Open H9 (1997)-295970) may be administered to homeotherm and biological samples may be collected from the animal after a predetermined time. Next, target compound(s) in the biological sample may be isolated and purified by any separation method such as column chromatography to obtain the compound(s) according to the present invention.
The term xe2x80x9chomeothermxe2x80x9d refers to an animal which is capable of thermoregulation to maintain its constant body temperature regardless of atmospheric temperature, including: warm blooded animals, e.g. mammals such as a human, dog, monkey, rabbit, guinea pig, rat or mouse; and birds such as a chicken.
The term xe2x80x9cbiological samplexe2x80x9d includes, for example, plasma, urine, feces (bile), liver and kidney.
The above-described compounds (I)-(IV) according to the present invention and pharmacologically acceptable salts, esters or amides thereof have the following activities: PPARxcex3 activation activity; insulin resistance improving activity; hypoglycemic activity; anti-inflammatory activity; immunoregulatory activity; aldose reductase inhibiting activity; 5-lipoxygenase inhibiting activity; inhibition of lipid peroxide expression; PPAR activation activity; anti-osteoporotic activity; leukotriene antagonistic activity; enhancement of adipose cell formation; inhibition of carcinoma cell proliferation; and calcium antagonistic activity. The present invention provides treatment and/or prevention of, for example: diabetes mellitus; hyperlipidemia; obesity; impaired glucose tolerance; hypertension; fatty liver; diabetic complications such as retinopathy, nephrosis, neuropathy, cataract or coronary artery disease; arteriosclerosis; gestational diabetes mellitus; polycystic ovary syndrome; cardiovascular diseases such as ischemic heart disease; cell injury lesions including those caused by non-atherosclerosis or ischemic heat disease such as cerebral injury caused by stroke; gout; inflammatory diseases such as arthrosteitis, pain, fervesence, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic disease, asthma, GI ulcer, cachexia, autoimmune disease and pancreatitis; cancer; osteoporosis; and cataract by administering to an animal (including a human) in need thereof, an effective amount of a compound of the formula (I)-(IV).
Further, pharmaceutical compositions which comprise at least one compound selected from the group consisting of the above-described compounds (I)-(IV) according to the present invention and pharmacologically acceptable salts, esters or amides thereof and at least one compound selected from the group consisting of RXR activators (RXR agonists), xcex1-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statine type compounds, squalene synthesis inhibitors, fibrate type compounds, LDL disassimilation promotors and angiotensin-converting enzyme-inhibitors (particularly preferable are compositions for prevention and/or treatment of diabetes or diabetic complication) are also useful.
The above-described compounds (I)-(IV) according to the present invention or pharmacologically acceptable salts, esters or amides thereof can be used for treatment or prevention of the above-described diseases by administering the compound alone or in combination with a suitable pharmacologically acceptable carrier in a suitable dosage form, such as tablets, capsules, granules, powders or syrups for oral administration, or injections or suppositories for parenteral administration. Other usual dosage forms, e.g., ointments and sprays, may be used for alternate administration routes.
Such formulations may be prepared according to any well known technique, and may also include carrier(s) such as excipients, lubricants, binders, disintegrators, stabilizers, corrigents and/or diluents. Excipients include both organic and inorganic excipients. Examples of organic excipients are, for example: glucose derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, ax starch and dextrin; cellulose derivatives such as crystalline cellulose; gum Arabic; dextran; and Pullulan. Examples of inorganic excipients are, for example: silicate derivatives such as light anhydrous silicic acid, synthetic aluminium silicate, calcium silicate and magnesium metaaluminosilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate. Lubricants include, for example: stearic acid and metal stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium fatty acid salt; lauryl sulfates such as lauryl sodium sulfate or lauryl magnesium sulfate; silicates such as silicic anhydride or silicic hydrate; and the above-described starch derivatives. Binders include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, Macrogol and the above-described excipient compounds. Disintegrators include, for example: cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, internal-crosslinked sodium carboxymethyl cellulose; chemically modified starch-cellulose compounds such as carboxymethyl starch, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone. Stabilizers include, for example: p-hydroxybenzoic esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid. Corrigents include sweeteners, souring agents and flavors which are commonly used in the art.
The dose will vary depending on the disease state, age of the patient, e.g. human, the chosen route of administration, etc. In the case of oral administration, a desirable single unit dose contains the compound of the present invention in an amount of 0.001 to 500 mg/kg of body weight and preferably from 0.01 to 50 mg/kg of body weight. In the case of intravenous administration, a desirable single unit dose contains the compound of the present invention in an amount of 0.005 to 50 mg/kg of body weight and preferably 0.05 to 5 mg/kg of body weight. It is desirable to administer the single unit dose one time or several times throughout the day depending on the conditions of the patient. Other dosage forms for other administration routes will also be within the aforesaid ranges and preferably in an amount of 0.01 to 50 mg/kg of body weight. Dosage for treatment or prevention of a specific patient in need thereof is determined by those skilled in the art by applying usual techniques.
The following examples, preparation examples and test examples are intended to further illustrate the present invention and are not intended to limit the scope of this invention.